Substituted heterocycle fused gamma-carbolines

ABSTRACT

The present invention is directed to certain novel compounds represented by structural Formula (I)                    
     or pharmaceutically acceptable salt forms thereof, wherein R 1 , R 5 , R 6a , R 6b , R 7 , R 8 , R 9 , X, b, k, m, and n, and the dashed lines are described herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are serotonin agonists and antagonists and are useful in the control or prevention of central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.

This application claims the benefit of U.S. Provisional Application No.60/139,321, filed Jun. 15, 1999.

FIELD OF THE INVENTION

The present invention is directed to certain novel compounds representedby structural Formula (I)

or pharmaceutically acceptable salt forms thereof, wherein R¹, R⁵,R^(6a), R^(6b), R⁷, R⁸, R⁹, X, b, k, m, and n, and the dashed lines aredescribed herein. The invention is also concerned with pharmaceuticalformulations comprising these novel compounds as active ingredients andthe use of the novel compounds and their formulations in the treatmentof certain disorders. The compounds of this invention are serotoninagonists and antagonists and are useful in the control or prevention ofcentral nervous system disorders including obesity, anxiety, depression,psychosis, schizophrenia, sleep disorders, sexual disorders, migraine,conditions associated with cephalic pain, social phobias, andgastrointestinal disorders such as dysfunction of the gastrointestinaltract motility.

BACKGROUND OF THE INVENTION

There exists a substantial correlation for the relationship between5-HT2 receptor modulation and a variety of diseases and therapies. Todate, three subtypes of the 5-HT2 receptor class have been identified,5-HT2A, 5-HT2B, and 5-HT2C. Prior to the early 1990's the 5-HT2C and5-HT2A receptors were referred to as 5-HT1C and 5-HT2, respectively.

The agonism or antagonism of 5-HT2 receptors, either selectively ornonselectively, has been associated with the treatment of variouscentral nervous system (CNS) disorders. Ligands possessing affinity forthe 5-HT2 receptors have been shown to have numerous physiological andbehavioral effects (Trends in Pharmacological Sciences, 11, 181, 1990).In the recent past the contribution of serotonergic activity to the modeof action of antidepressant drugs has been well documented. Compoundsthat increase the overall basal tone of serotonin in the CNS have beensuccessfully developed as antidepressants. The serotonin selectivereuptake inhibitors (SSRI) function by increasing the amount ofserotonin present in the nerve synapse. These breakthrough treatments,however, are not without side effects and suffer from delayed onset ofaction (Leonard, J. Clin. Psychiatry, 54(suppl), 3, 1993). Due to themechanism of action of the SSRIs, they effect the activity of a numberof serotonin receptor subtypes. This non-specific modulation of theserotonin family of receptors most likely plays a significant role inthe side effect profile. In addition, these compounds often have a highaffinity for a number of the serotonin receptors as well as a multitudeof other monoamine neurotransmitters and nuisance receptors. Removingsome of the receptor cross reactivity would allow for the examinationand possible development of potent therapeutic ligands with an improvedside effect profile.

There is ample evidence to support the role of selective 5-HT2 receptorligands in a number of disease therapies. Modulation of 5-HT2 receptorshas been associated with the treatment of schizophrenia and psychoses(Ugedo, L., et. al., Psychopharmacology, 98, 45, 1989). Mood, behaviorand hallucinogenesis can be affected by 5-HT2 receptors in the limbicsystem and cerebral cortex. 5-HT2 receptor modulation in thehypothalamus can influence appetite, thermoregulation, sleep, sexualbehavior, motor activity, and neuroendocrine function (Hartig, P.,et.al., Annals New York Academy of Science, 149, 159). There is alsoevidence indicating that 5-HT2 receptors mediate hypoactivity, effectfeeding in rats, and mediate penile erections (Pyschopharmacology, 101,57, 1990).

Compounds exhibiting selectivity for the 5-HT2B receptor are useful intreating conditions such as tachygastria, hypermotility associated withirritable bowel disorder, constipation, dyspepsia, and otherperipherally mediated conditions.

5-HT2A antagonists have been shown to be effective in the treatment ofschizophrenia, anxiety, depression, and migraines (Koek, W.,Neuroscience and Behavioral reviews, 16, 95, 1996). Aside from thebeneficial antipsychotic effects, classical neuroleptic are frequentlyresponsible for eliciting acute extrapyramidal side effects andneuroendocrine disturbances. These compounds generally possesssignifcant dopamine D2 receptor affinity (as well as other nuisancereceptor affinity) which frequently is associated with extra pyramidalsymptoms and tardive dyskinesia, thus detracting from their efficacy asfront line treatments in schizophrenia and related disorders. Compoundspossessing a more favorable selectivity profile would represent apossible improvement for the treatment of CNS disorders.

U.S. Pat. Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936; and 4,238,607disclose pyridopyrrolobenzheterocycles of formula:

where X is O, S, S(═O), or SO₂; n is 0 or 1; R¹ is various carbonsubstituents, and Z is a monosubstituent of H, methyl, or chloro.

U.S. Pat. No. 4,219,550 discloses pyridopyrrolobenzheterocycles offormula:

where X is O or S; R¹ is C₁₋₄ alkyl or cyclopropyl; R² is H, CH₃, OCH₃,Cl, Br, F, or CF₃; and (A) is —CH₂—, —CH(CH₃)—, or —CH₂CH₂—.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel compounds whichare useful as agonists or antagonists of 5-HT2 receptors, morespecifically 5-HT2A and 5-HT2C receptors, or pharmaceutically acceptablesalts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating central nervous system disorders including obesity, anxiety,depression, psychosis, schizophrenia, sleep and sexual disorders,migraine and other conditions associated with cephalic pain, socialphobias, and gastrointestinal disorders such as dysfunction of thegastrointestinal tract motility comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof. More specifically, the presentinvention provides a method for treating obesity anxiety, depression, orschizophrenia.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of Formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, whereinR¹, R⁵, R^(6a), R_(6b), R⁷, R⁸, R⁹, X, b, k, m, and n are defined below,are effective agonists or antagonists of 5-HT2 receptors.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Thus, in a first embodiment, the present invention provides a novelcompound of Formula (I):

or stereoisomers or pharmaceutically acceptable salt forms thereof,wherein:

b is a single bond or a double bond;

X is —CHR¹⁰—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(10A)—,—C(═O)NR^(10A)—, or —NR^(10A)C(═O)—;

R¹ is selected from

H

C(═O)R²,

C(═O)OR²,

C₁₋₈ alkyl,

C₂₋₈ alkenyl,

C₂₋₈ alkynyl,

C₃₋₇ cycloalkyl,

C₁₋₆ alkyl substituted with Z,

C₂₋₆ alkenyl substituted with Z,

C₂₋₆ alkynyl substituted with Z,

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z;

C₁₋₃ alkyl substituted with Y,

C₂₋₃ alkenyl substituted with Y,

C₂₋₃ alkynyl substituted with Y,

C₁₋₆ alkyl substituted with 0-2 R²,

C₂₋₆ alkenyl substituted with 0-2 R²,

C₂₋₆ alkynyl substituted with 0-2 R²,

aryl substituted with 0-2 R², and

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with 0-2 R²;

Y is selected from

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with z;

C₃₋₆ cycloalkyl substituted with —(C₁₋₃ alkyl)-Z,

aryl substituted with —(C₁₋₃ alkyl)-Z, and

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with —(C₁₋₃ alkyl)-Z;

Z is selected from H,

—CH(OH)R²,

—C(ethylenedioxy)R²,

—OR²,

—SR²,

—NR²R³,

—C(O)R²,

—C(O)NR²R³,

—NR³C(O)R²,

—C(O)OR²,

—OC(O)R²,

—CH(═NR⁴)NR²R³,

—NHC(═NR⁴)NR²R³,

—S(O)R²,

—S(O)₂R²,

—S(O)₂NR²R³, and —NR³S(O)₂R²;

R², at each occurrence, is independently selected from

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-5 R⁴²;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R² and R³ join to form a 5- or 6-membered ring optionallysubstituted with —O— or —N(R⁴)—;

R⁴, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁵ is H or C₁₋₄ alkyl;

R^(6a) and R^(6b), at each occurrence, are independently selected from

H, —OH, —NR⁴⁶R⁴⁷, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, and

aryl substituted with 0-3 R⁴⁴;

R⁷ and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl, substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, aryl substitutedwith 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)R¹³, C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²;

R⁸ is selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl, substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)R¹³, C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²;

R¹⁰ is selected from H, —OH,

C₁₋₆ alkyl substituted with 0-1 R^(10B),

C₂₋₆ alkenyl substituted with 0-1 R^(10B),

C₂₋₆ alkynyl substituted with 0-1 R^(10B), and

C₁₋₆ alkoxy;

R^(10A) is selected from H,

C₁₋₆ alkyl substituted with 0-1 R^(10B),

C₂₋₆ alkenyl substituted with 0-1 R^(10B),

C₂₋₆ alkynyl substituted with 0-1 R^(10B), and

C₁₋₆ alkoxy;

R^(10B) is selected from

C₁₋₄ alkoxy,

C₃₋₆ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

phenyl substituted with 0-3 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴;

R¹¹ is selected from

H, halo, —CF₃, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,C₃₋₁₀ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)R¹³, C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²; p0R¹², at each occurrence, is independently selected from

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

R¹⁴, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, and C₁₋₄ alkyl-C(═O)NH—;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN;

C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴², and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶SO₂R⁴⁵, NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN,CH(═NH)NH₂, NHC(═NH)NH₂,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴⁴, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H,

halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl,and C₁₋₄ alkoxy;

R⁴⁵ is C₁₋₄ alkyl;

R⁴⁶, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R⁴⁷, at each occurrence, is independently selected from H and C₁₋₄alkyl;

k is 1 or 2;

m is 0, 1, 2, or 3;

n is 0, 1, or 2;

provided when m is 0, then k is 1;

provided that when b is a double bond; n is 1 or 2; m is 1; k is 1; X is—O—, —S—, —S(═O)—, or —SO₂—; and the three substituents of R⁷, R⁸, andR⁹, consist of i) three hydrogens, ii) two hydrogens and one chloro, oriii) two hydrogens and one methyl; then R¹ must contain the substituentZ or Y;

provided that when b is a double bond; n is 0 or 1; m is 1; k is 1; X is—CH₂—; and R¹ is hydrogen, C₁₋₆ alkyl or benzyl; then one of R⁷, R8, andR⁹, must be other than hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy ortrifluoromethyl;

provided that when b is a single bond; n is 1 or 2; m is 1; k is 1; X isO or S; and R¹ is C₁₋₄ alkyl or cyclopropyl, then R⁸ is a substituentother than H;

provided that when R⁶ or R^(6a) is NH₂, then X is not —CH(R¹⁰); and

provided that when n═0, then R⁶ or R^(6a) is not NH₂ or —OH.

In another embodiment of the present invention,

X is —CHR¹⁰—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)NH—, or—NHC(═O)—;

R¹ is selected from

H,

C(═O)R²,

C(═O)OR²,

C₁₋₈ alkyl,

C₂₋₈ alkenyl,

C₂₋₈ alkynyl,

C₃₋₇ cycloalkyl,

C₁₋₆ alkyl substituted with Z,

C₂₋₆ alkenyl substituted with Z,

C₂₋₆ alkynyl substituted with Z,

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z;

C₁₋₃ alkyl substituted with Y,

C₂₋₃ alkenyl substituted with Y,

C₂₋₃ alkynyl substituted with Y,

C₁₋₆ alkyl substituted with 0-2 R²,

C₂₋₆ alkenyl substituted with 0-2 R²,

C₂₋₆ alkynyl substituted with 0-2 R²,

aryl substituted with 0-2 R², and

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with 0-2 R²;

Y is selected from

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z;

C₃₋₆ cycloalkyl substituted with —(C₁₋₃ alkyl)-Z,

aryl substituted with —(C₁₋₃ alkyl)-Z, and

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with —(C₁₋₃ alkyl)-Z;

Z is selected from H,

—CH(OH)R²,

—C(ethylenedioxy)R²,

—OR²,

—SR²R³,

—NR²R³,

—C(O)R²,

—C(O)NR²R³,

—NR³C(O)R²,

—C(O)OR²,

—OC(O)R²,

—CH(═NR⁴)NR²R³,

—NHC(═NR⁴)NR²R³,

—S(O)R²,

—S(O)₂R²,

—S(O)₂NR²R³, and —NR³S(O)₂R²;

R², at each occurrence, is independently selected from

halo,

C₁₋₃ haloalkyl,

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

aryl substituted with 0-5 R⁴²;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄ alkoxy;

alternatively, R² and R³ join to form a 5- or 6-membered ring optionallysubstituted with —O— or —N(R⁴)—;

R⁴, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁵ is H or C₁₋₄ alkyl;

R^(6a) and R^(6b), at each occurrence, are independently selected from

H, —OH, —NR⁴⁶R⁴⁷, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, and

aryl substituted with 0-3 R⁴⁴;

R⁷ and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O) NHR¹⁵;

R⁸ is selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₂₋₄ alkenyl substituted with 0-2 R¹¹,

C₂₋₄ alkynyl substituted with 0-1 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R^(10A) is selected from H,

C₁₋₆ alkyl substituted with 0-1 R^(10B),

C₂₋₆ alkenyl substituted with 0-1 R^(10B),

C₂₋₆ alkynyl substituted with 0-1 R^(10B), and

C₁₋₆ alkoxy;

R^(10B) is selected from

C₁₋₄ alkoxy,

C₃₋₆ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

phenyl substituted with 0-3 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴;

R¹¹ is selected from

H, halo, —CF₃, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,C₃₋₁₀ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R^(13, NR) ¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R¹² at each occurrence, is independently selected from

C₁₋₄ alkyl substituted with 0-1 R^(12a),

C₂₋₄ alkenyl substituted with 0-1 R^(12a),

C₂₋₄ alkynyl substituted with 0-1 R^(12a),

C₃₋₆ cycloalkyl substituted with 0-3 R³³,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R^(12a), at each occurrence, is independently selected from

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

alternatively, R¹² and R¹³ when attached to N may be combined to form a9- or 10-membered bicyclic heterocyclic ring system containing from 1-3heteroatoms selected from the group consisting of N, O, and S, whereinsaid bicyclic heterocyclic ring system is unsaturated or partiallysaturated, wherein said bicyclic heterocyclic ring system is substitutedwith 0-3 R¹⁶;

R¹⁴, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R¹⁵, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹⁶, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,

C₁₋₃ haloalkyl-oxy-, and C₁₋₃ alkyloxy-;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

C₁₋₄ alkyloxy-,

C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—,

C₁₋₄ alkyl-OC(═O)—,

C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆

cycloalkylmethyl-oxy-;

C₁₋₆ alkyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy; and

C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O;

C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl C₁₋₄ alkylsubstituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴², and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵, NR⁴⁶SO₂R⁴⁵, NR⁴⁶COR⁴⁵,NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴⁴, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H,

halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂,

C₁₋₄ alkyl, and C₁₋₄ alkoxy;

R⁴⁵ is C₁₋₄ alkyl;

R⁴⁶, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R⁴⁷, at each occurrence, is independently selected from H,

C₁₋₄ alkyl, —C(═O) NH (C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl) —C(═O)O(C₁₋₄alkyl), —C(═O)( C₁₋₄ alkyl), and —C(═O)H;

k is 1 or 2;

m is 0, 1, or 2;

n is 1, 2, or 3;

provided when m is 0 or 1 then k is 1 or 2;

provided when m is 2 then k is 1;

provided that when n═O, then R⁶ or R^(6a) is not NH₂ or —OH.

(2) In a preferred embodiment of the present invention,

X is —NR^(10A)—, —C(═O)NR^(10A)—, or —NR^(10A)C(═O)—;

R¹ is selected from

H,

C(═O)R²,

C(═O)OR²,

C₁₋₈ alkyl,

C₂₋₈ alkenyl,

C₂₋₈ alkynyl,

C₃₋₇ cycloalkyl,

C₁₋₆ alkyl substituted with Z,

C₂₋₆ alkenyl substituted with Z,

C₂₋₆ alkynyl substituted with Z,

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z;

C₁₋₃ alkyl substituted with Y,

C₂₋₃ alkenyl substituted with Y,

C₂₋₃ alkynyl substituted with Y,

C₁₋₆ alkyl substituted with 0-2 R²,

C₂₋₆ alkenyl substituted with 0-2 R²,

C₂₋₆ alkynyl substituted with 0-2 R²,

aryl substituted wit h 0-2 R², and

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with 0-2 R²;

Y is selected from

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z; C₃₋₆ cycloalkyl substituted with ·(C₁₋₃alkyl)-Z, aryl substituted with ·(C₁₋₃ alkyl)-Z, and 5-6 memberedheterocyclic ring system containing at least one heteroatom selectedfrom the group consisting of N, O, and S, said heterocyclic ring systemsubstituted with ·(C₁₋₃ alkyl)-Z;

Z is selected from H,

—CH(OH)R²,

—C(ethylenedioxy)R²,

—OR²,

—SR²R³,

—C(O)R²

—C(O)NR²R³,

—NR³C(O)R²,

—C(O)OR²,

—OC(O)R²,

—CH(═NR⁴)NR²R³,

—NHC(═NR⁴)NR²R³,

—S(O)R²,

—S(O)₂R²,

—S(O)₂NR²R³, and —NR³S(O)₂R²;

R², at each occurrence, is independently selected from

halo,

C₁₋₃ haloalkyl,

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

aryl substituted with 0-5 R⁴²;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and

C₁₋₄ alkoxy;

alternatively, R² and R³ join to form a 5- or 6-membered ring optionallysubstituted with —O— or —N(R⁴)—;

R⁴, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁵ is H or C₁₋₄ alkyl;

R^(6a) and R^(6b), at each occurrence, are independently selected from

H, —OH, —NR⁴⁶R⁴⁷, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, and

aryl substituted with 0-3 R⁴⁴;

R⁷ and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴CCO)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵ NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R⁸ is selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₂₋₄ alkenyl substituted with 0-2 R¹¹,

C₂₋₄ alkynyl substituted with 0-1 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O) NHR¹⁵;

R^(10A) is selected from H,

C₁₋₆ alkyl substituted with 0-1 R^(10B),

C₂₋₆ alkenyl substituted with 0-1 R^(10B),

C₂₋₆ alkynyl substituted with 0-1 R^(10B), and

C₁₋₆ alkoxy;

R^(10B) is selected from

C₁₋₄ alkoxy,

C₃₋₆ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

phenyl substituted with 0-3 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴;

R¹¹ is selected from

H, halo, —CF₃, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,C₃₋₁₀ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂, R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R¹², at each occurrence, is independently selected from

C₁₋₄ alkyl substituted with 0-1 R^(12a),

C₂₋₄ alkenyl substituted with 0-1 R^(12a),

C₂₋₄ alkynyl substituted with 0-1 R^(12a),

C₃₋₆ cycloalkyl substituted with 0-3 R³³,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R^(12a), at each occurrence, is independently selected from

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

alternatively, R¹² and R¹³ when attached to N may be combined to form a9- or 10-membered bicyclic heterocyclic ring system containing from 1-3heteroatoms selected from the group consisting of N, O, and S, whereinsaid bicyclic heterocyclic ring system is unsaturated or partiallysaturated, wherein said bicyclic heterocyclic ring system is substitutedwith 0-3 R¹⁶;

R¹⁴, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R¹⁵, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹⁶, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,

C₁₋₃ haloalkyl-oxy-, and C₁₋₃ alkyloxy-;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

C₁₋₄ alkyloxy-,

C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—,

C₁₋₄ alkyl-OC(═O)—,

C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-;

C₁₋₆ alkyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy; and

C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O;

C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴², and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵, NR⁴⁶SO₂R⁴⁵, NR⁴⁶COR⁴⁵,NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴⁴, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H,

halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂,

C₁₋₄ alkyl, and C₁₋₄ alkoxy;

R⁴⁵ is C₁₋₄ alkyl;

R⁴⁶, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R⁴⁷, at each occurrence, is independently selected from H,

C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl),

—C(═O)O(C₁₋₄ alkyl), —C(═O)( C₁₋₄ alkyl), and —C(═O)H;

k is 1 or 2;

m is 0, 1, or 2;

n is 1, 2, or 3;

provided when m is 0 or 1 then k is 1 or 2;

provided when m is 2 then k is 1;

provided that when n═0, then R⁶ or R^(6a) is not NH₂ or —OH.

In a further preferred embodiment of the present invention,

X is —NR^(10A)—, —C(═O)NH—, or —NHC(═O)—;

R¹ is selected from

H,

C(═O)R²,

C(═O)OR²,

C₁₋₈ alkyl,

C₂₋₈ alkenyl,

C₂₋₈ alkynyl,

C₃₋₇ cycloalkyl,

C₁₋₆ alkyl substituted with 0-2 R²,

C₂₋₆ alkenyl substituted with 0-2 R²,

C₂₋₆ alkynyl substituted with 0-2 R²,

aryl substituted with 0-2 R², and

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with 0-2 R²;

R², at each occurrence, is independently selected from

F, Cl, CH₂F, CHF₂, CF₃,

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-5 R⁴²;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R⁵ is H, methyl, ethyl, propyl, or butyl;

R^(6a) is selected from

H, —OH, —NR⁴⁶R⁴⁷, —CF₃,

C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and

aryl substituted with 0-3 R⁴⁴;

R^(6b) is H;

R⁷ and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R⁸ is selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₂₋₄ alkenyl substituted with 0-2 R¹¹,

C₂₋₄ alkynyl substituted with 0-1 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R^(10A) is selected from H,

C₁₋₆ alkyl substituted with 0-1 R^(10B),

C₂₋₆ alkenyl substituted with 0-1 R^(10B),

C₂₋₆ alkynyl substituted with 0-1 R^(10B), and

C₁₋₆ alkoxy;

R^(10B) is selected from

C₁₋₄ alkoxy,

C₃₋₆ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

phenyl substituted with 0-3 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴;

R¹¹ is selected from

H, halo, —CF₃, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,C₃₋₁₀ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R¹², at each occurrence, is independently selected from

C₁₋₄ alkyl substituted with 0-1 R^(12a),

C₂₋₄ alkenyl substituted with 0-1 R^(12a),

C₂₋₄ alkynyl substituted with 0-1 R^(12a),

C₃₋₆ cycloalkyl substituted with 0-3 R³³,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R^(12a), at each occurrence, is independently selected from

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

alternatively, R¹² and R¹³ when attached to N may be combined to form a9- or 10-membered bicyclic heterocyclic ring system containing from 1-3heteroatoms selected from the group consisting of N, O, and S, whereinsaid bicyclic heterocyclic ring system is unsaturated or partiallysaturated, wherein said bicyclic heterocyclic ring system is substitutedwith 0-3 R¹⁶;

R¹⁴, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R¹⁵, at each occurrence, is independently selected from

H, C¹⁻⁴ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹⁶, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,

C₁₋₃ haloalkyl-oxy-, and C₁₋₃ alkyloxy-;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

C₁4 alkyloxy-,

C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—,

C₁₋₄ alkyl-OC(═O)—,

C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-;

C₁₋₆ alkyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy; and

C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN;

C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl C₁₋₄ alkylsubstituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴², and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴⁴, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H, halo, —OH,NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy;

R⁴⁵ is C₁₋₄ alkyl;

R⁴⁶, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R⁴⁷, at each occurrence, is independently selected from H and C₁₋₄alkyl;

k is 1 or 2;

m is 0, 1, or 2; and

n is 1, 2, or 3.

[4] In a more preferred embodiment of the present invention,

X is —NR^(10A)—;

R¹ is selected from

H,

C(═O)R²,

C(═O)OR²,

C₁₋₆ alkyl,

C₂₋₆ alkenyl,

C₂₋₆ alkynyl,

C₃₋₆ cycloalkyl,

C₁₋₄ alkyl substituted with 0-2 R²,

C₂₋₄ alkenyl substituted with 0-2 R², and

C₂₋₄ alkynyl substituted with 0-2 R²;

R², at each occurrence, is independently selected from

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-5 R⁴²;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R⁵ is H, methyl, ethyl, propyl, or butyl;

R^(6a) is selected independently from

H, —OH, —NR⁴⁶R⁴⁷, —CF₃, C₁₋₃ alkyl, and C₁₋₃ alkoxy;

R^(6b) is H;

R⁷ and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,SO(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²;

R⁸ is selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₂₋₄ alkenyl substituted with 0-2 R¹¹,

C₂₋₄ alkynyl substituted with 0-1 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R^(10A) is selected from H,

C₁₋₄ alkyl substituted with 0-1 R^(10B),

C₂₋₄ alkenyl substituted with 0-1 R^(10B),

C₂₋₄ alkynyl substituted with 0-1 R^(10B), and

C₁₋₆ alkoxy;

R^(10B) is selected from

C₁₋₄ alkoxy,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-3 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴;

R¹¹ is selected from

H, halo, —CF₃, —CN, —NO₂, C₁₋₆ alkyl,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₆ alkoxy, C₃₋₁₀cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, (O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²;

R¹², at each occurrence, is independently selected from

C₁₋₄ alkyl substituted with 0-1 R^(12a),

C₂₋₄ alkenyl substituted with 0-1 R^(12a),

C₂₋₄ alkynyl substituted with 0-1 R^(12a),

C₃₋₆ cycloalkyl substituted with 0-3 R³³,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R^(12a), at each occurrence, is independently selected from

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

alternatively, R¹² and R¹³ when attached to N may be combined to form a9- or 10-membered bicyclic heterocyclic ring system containing from 1-3heteroatoms selected from the group consisting of N, O, and S, whereinsaid bicyclic heterocyclic ring system is unsaturated or partiallysaturated, wherein said bicyclic heterocyclic ring system is substitutedwith 0-3 R¹⁶;

R¹⁴, at each occurrence, is independently selected from H, methyl,ethyl, propyl, and butyl;

R¹⁵, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹⁶, at each occurrence, is independently selected from

H, OH, F, Cl, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and

trifluoromethoxy;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

C₁₋₄ alkyloxy-,

C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—,

C₁₋₄ alkyl-OC(═O)—,

C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆

cycloalkylmethyl-oxy-;

C₁₋₆ alkyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy; and

C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN,

C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴², and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴⁴, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H, halo, —OH,NR⁴⁶R⁴⁷, C₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy;

R⁴⁵ is C₁₋₄ alkyl;

R⁴⁶, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R⁴⁷, at each occurrence, is independently selected from H and C₁₋₄alkyl;

k is 1 or 2;

m is 0 or 1; and

n is 1 or 2.

[5] In an even more preferred embodiment of the present invention,

X is —NH—;

R¹ is selected from

H,

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₄ cycloalkyl,

C₁₋₃ alkyl substituted with 0-1 R²,

C₂₋₃ alkenyl substituted with 0-1 R², and

C₂₋₃ alkynyl substituted with 0-1 R²;

R², at each occurrence, is independently selected from

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-5 R⁴²;

C₃₋₆ carbocyclic residue substituted with 0-3 R⁴¹, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R⁵ is H, methyl, ethyl, propyl, or butyl;

R^(6a) is H, methyl, ethyl, methoxy, —OH, or —CF₃;

R^(6b) is H;

R⁷ and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R⁸ is selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₂₋₄ alkenyl substituted with 0-2 R¹¹,

C₂₋₄ alkynyl substituted with 0-1 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, andNR¹²C(O)NHR¹⁵;

R¹¹ is selected from

H, halo, —CF₃, —CN, —NO₂,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹², at each occurrence, is independently selected from

C₁₋₄ alkyl substituted with 0-1 R^(12a),

C₂₋₄ alkenyl substituted with 0-1 R^(12a),

C₂₋₄ alkynyl substituted with 0-1 R^(12a),

C₃₋₆ cycloalkyl substituted with 0-3 R³³,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R^(12a), at each occurrence, is independently selected from

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

alternatively, R¹² and R¹³ when attached to N may be combined to form a9- or 10-membered bicyclic heterocyclic ring system containing from 1-3heteroatoms selected from the group consisting of one N, two N, three N,one N one O, and one N one S; wherein said bicyclic heterocyclic ringsystem is unsaturated or partially saturated, wherein said bicyclicheterocyclic ring system is substituted with 0-2 R¹⁶;

R¹⁴, at each occurrence, is independently selected from H, methyl,ethyl, propyl, and butyl;

R¹⁵, at each occurrence, is independently selected from H, methyl,ethyl, propyl, and butyl;

R¹⁶, at each occurrence, is independently selected from

H, OH, F, Cl, CN, NO₂, methyl, ethyl, methoxy, ethoxy,

trifluoromethyl, and trifluoromethoxy;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, methyl, ethyl, and propyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

C₁₋₄ alkyloxy-,

C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—,

C₁₋₄ alkyl-OC(═O)—,

C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-;

C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and

C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN,

C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ alkyl;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, and C₁₋₃ alkyl;

R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, orpyridyl, each substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H,

halo, —OH, NR⁴⁶R⁴⁷, C₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂,

methyl, ethyl, propyl, butyl, methoxy, ethoxy,

propoxy, and butoxy;

R⁴⁵ is methyl, ethyl, propyl, or butyl;

R⁴⁶, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R⁴⁷, at each occurrence, is independently selected from

from H, methyl, ethyl, propyl, and butyl;

k is 1;

m is 1; and

n is 1 or 2.

[6] In another even more preferred embodiment of the present invention,

X is —NH—;

R¹ is selected from

H,

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₄ cycloalkyl,

C₁₋₃ alkyl substituted with 0-1 R²,

C₂₋₃ alkenyl substituted with 0-1 R², and

C₂₋₃ alkynyl substituted with 0-1 R²;

R², at each occurrence, is independently selected from

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-5 R⁴²;

C₃₋₆ carbocyclic residue substituted with 0-3 R⁴¹, and 5-6 memberedheterocyclic ring system containing 1, 2, or 3 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R⁴¹;

R⁵ is H, methyl, ethyl, propyl, or butyl;

R^(6a) is H, methyl, ethyl, methoxy, —OH, or —CF₃;

R^(6b) is H;

R⁷ and R⁹, at each occurrence, are independently selected from

H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂,

R⁸ is selected from

H, F, Cl, Br, —CF₃, —OCF₃, —OH, —CN, —NO₂,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₂₋₄ alkenyl substituted with 0-2 R¹¹,

C₂₋₄ alkynyl substituted with 0-1 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, andNR¹²C(O) NHR¹⁵;

R¹¹is selected from

H, halo, —CF₃, —CN, —NO₂,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹², at each occurrence, is independently selected from

C₁₋₄ alkyl substituted with 0-1 R^(12a),

C₂₋₄ alkenyl substituted with 0-1 R^(12a),

C₂₋₄ alkynyl substituted with 0-1 R^(12a),

C₃₋₆ cycloalkyl substituted with 0-3 R³³,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R^(12a), at each occurrence, is independently selected from

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

alternatively, R¹² and R¹³ when attached to N may be combined to form a9- or 10-membered bicyclic heterocyclic ring system containing from 1-3heteroatoms selected from the group consisting of N, O, and S; whereinsaid bicyclic heterocyclic ring system is selected from indolyl,indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl,benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl;wherein said bicyclic heterocyclic ring system is substituted with 0-1R¹⁶;

R¹⁴, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R¹⁵, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R¹⁶, at each occurrence, is independently selected from

H, OH, F, Cl, CN, NO₂, methyl, ethyl, methoxy, ethoxy,

trifluoromethyl, and trifluoromethoxy;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, methyl, ethyl, and propyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

C₁₋₄ alkyloxy-,

C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—,

C₁₋₄ alkyl-OC(═O)—,

C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-;

C₁₋₆ alkyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy; and

C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy,

propoxy, or butoxy;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, C₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN,

C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ alkyl;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, and C₁₋₃ alkyl;

R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

phenyl, or pyridyl, each substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H,

halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂,

methyl, ethyl, propyl, butyl, methoxy, ethoxy,

propoxy, and butoxy;

R⁴⁵ is methyl, ethyl, propyl, or butyl;

R⁴⁶, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R⁴⁷, at each occurrence, is independently selected from

from H, methyl, ethyl, propyl, and butyl;

k is 1;

m is 1; and

n is 1 or 2.

[7] In another even more preferred embodiment of the present invention,

X is —NH—;

R¹ is selected from H,

C₁₋₅ alkyl substituted with 0-1 R²,

C₂₋₅ alkenyl substituted with 0-1 R², and

C₂₋₃ alkynyl substituted with 0-1 R²;

R² is C₃₋₆ cycloalkyl;

R⁵ is H, methyl, ethyl, or propyl;

R^(6a) is H, methyl, or ethyl;

R^(6b) is H;

R⁷ and R⁹, at each occurrence, are independently selected from

H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂,

R⁸ is selected from

methyl substituted with R¹¹;

ethenyl substituted with R¹¹;

OR¹², SR¹², NR¹²R¹³, NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,

NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R¹¹ is selected from

phenyl-substituted with 0-5 fluoro;

2-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

2-(H₃CC(═O))-phenyl-substituted with R³³;

2-(HC(═O))-phenyl-substituted with R³³;

2-(H₃CCH(OH))-phenyl-substituted with R³³;

2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

2-(HOCH₂)-phenyl-substituted wit h R³³;

2-(HOCH₂CH₂)-phenyl-substituted with R³³;

2-(H₃COCH₂)-phenyl-substituted with R³³;

2-(H₃COCH₂CH₂)-phenyl-substituted with R³³;

2-(H₃CCH(OMe))-phenyl-substituted with R³³;

2-(H₃COC(═O))-phenyl-substituted with R³³;

2-(HOCH₂CH═CH)-phenyl-substituted with R³³;

2-((MeOC═O)CH═CH)-phenyl-substituted with R³³;

2-(methyl)-phenyl-substituted with R³³;

2-(ethyl)-phenyl-substituted with R³³;

2-(i-propyl)-phenyl-substituted with R³³;

2-(F₃C)-phenyl-substituted with R³³;

2-(NC)-phenyl-substituted with R³³;

2-(H₃CO)-phenyl-substituted with R³³;

2-(fluoro)-phenyl-substituted with R³³;

2-(chloro)-phenyl-substituted with R³³;

3-(NC)-phenyl-substituted with R³³;

3-(H₃CO)-phenyl-substituted with R³³;

3-(fluoro)-phenyl-substituted with R³³;

3-(chloro)-phenyl-substituted with R³³;

4-(NC)-phenyl-substituted with R³³;

4-(fluoro)-phenyl-substituted with R³³;

4-(chloro)-phenyl-substituted with R³³;

4-(H₃CS)-phenyl-substituted with R³³;

4-(H₃CS)-phenyl-substituted with R³³;

4-(ethoxy)-phenyl-substituted with R³³;

4-(i-propoxy)-phenyl-substituted with R³³;

4-(i-butoxy)-phenyl-substituted with R³³;

4-(H₃CCH₂CH₂C(═O))-phenyl-substituted with R³³;

4-((H₃C)₂CHC(═O))-phenyl-substituted with R³³;

4-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

4-(H₃CC(═O))-phenyl-substituted with R³³;

4-(H₃CCH₂CH₂CH(OH))-phenyl-substituted with R³³;

4-((H₃C)₂CHCH(OH))-phenyl-substituted with R³³;

4-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

4-(H₃CCH(OH))-phenyl-substituted with R³³;

4-(cyclopropyloxy)-phenyl-substituted with R³³;

4-(cyclobutyloxy)-phenyl-substituted with R³³; and

4-(cyclopentyloxy)-phenyl-substituted with R³³;

R¹² is selected from

phenyl-substituted with 0-5 fluoro;

2-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

2-(H₃CC(═O))-phenyl-substituted with R³³;

2-(HC(═O))-phenyl-substituted with R³³;

5 2-(H₃CCH(OH))-phenyl-substituted with R³³;

2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

2-(HOCH₂)-phenyl-substituted with R³³;

2-(HOCH₂CH₂)-phenyl-substituted with R³³;

2-(H₃COCH₂)-phenyl-substituted with R³³;

2-(H₃COCH₂CH₂)-phenyl-substituted with R³³;

2-(H₃CCH(OMe))-phenyl-substituted with R³³;

2-(H₃COC(═O))-phenyl-substituted with R³³;

2-(HOCH₂CH═CH)-phenyl-substituted with R³³;

2-((MeOC═O)CH═CH)-phenyl-substituted with R³³;

2-(methyl)-phenyl-substituted with R³³;

2-(ethyl)-phenyl-substituted with R³³;

2-(i-propyl)-phenyl-substituted with R³³;

2-(F₃C)-phenyl-substituted with R³³;

2-(NC)-phenyl-substituted with R³³;

2-(H₃CO)-phenyl-substituted with R³³;

2-(fluoro)-phenyl-substituted with R³ ³;

2-(choloro)-phenyl-substituted with R³³;

3-(NC)-phenyl-substituted with R³³;

3-(H₃CO)-phenyl-substituted with R³³;

3-(floro)-phenyl-substituted with R³³;

3-(chloro)-phenyl-substituted with R^(33;)

4-(NC)-phenyl-substituted with R³³;

4-(fluoro)-phenyl-substituted with R³³;

4-(choloro)-phenyl-substituted with R³³;

4-(H₃CS)-phenyl-substituted with R³³;

4-(H₃CO)-phenyl-substituted with R³³;

4-(ethoxy)-phenyl-substituted with R³³;

4-(i-propoxy)-phenyl-substituted with R³³;

4-(i-butoxy)-phenyl-substituted with R³³;

4-(H₃CCH₂CH₂C(═O))-phenyl-substituted with R³³;

4-( (H₃C)₂CHC(═O))-phenyl-substituted with R³³;

4-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

4-(H₃CC(═O))-phenyl-substituted with R³³;

4-(H₃CCH₂CH₂CH(OH))-phenyl-substituted with R³³;

4-((H₃C)₂CHCH(OH))-phenyl-substituted with R³³;

4-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

4-(H₃CCH(OH))-phenyl-substituted with R³³;

4-(cyclopropyloxy)-phenyl-substituted with R³³.;

4-(cyclobutyloxy)-phenyl-substituted with R³³; and

4-(cyclopentyloxy)-phenyl-substituted with R³³;

R¹³ is H, methyl, or ethyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ring selectedfrom pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl, piperizinyl,methylpiperizinyl,and morpholinyl;

alternatively, R¹² and R¹³ when attached to N may be combined to form a9- or 10-membered bicyclic heterocyclic ring system containing from 1-3heteroatoms selected from the group consisting of N, O, and S; whereinsaid bicyclic heterocyclic ring system is selected from indolyl,indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl,benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl;wherein said bicyclic heterocyclic ring system is substituted with 0-1R¹⁶;

R¹⁵ is H, methyl, ethyl, propyl, or butyl;

R¹⁶, at each occurrence, is independently selected from

H, OH, F, Cl, CN, NO₂, methyl, ethyl, methoxy, ethoxy,

trifluoromethyl, and trifluoromethoxy;

R³³, at each occurrence, is independently selected from

H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂;

k is 1;

m is 1; and

n is 1 or 2.

[8] In an even more preferred embodiment of the present invention, thecompound of Formula (I) is selected from Formula (I-a):

wherein:

b is a single bond or a double bond;

X is —NR^(10A)—;

R¹ is selected from

hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl,

t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,

2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl,

2-ethylbutyl, 3-methylpentyl, 3-methylbutyl,

4-methylpentyl, 2-fluoroethyl, 2,2-difluoroethyl,

2,2,2-trifluoroethyl,

2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl,

3-methyl-butenyl, 3-butenyl, trans-2-pentenyl,

cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,

3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl,

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,

cyclohexylmethyl,

benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,

2,5-dimethylbenzyl, 2,4-dimethylbenzyl, 3,5-dimethylbenzyl,

2,4,6-trimethyl-benzyl, 3-methoxy-benzyl, 3,5-dimethoxybenzyl,pentafluorobenzyl, 2-phenylethyl, 1-phenyl-2-propyl, 4-phenylbutyl,4-phenylbenzyl, 2-phenylbenzyl,

(2,3-dimethoxy-phenyl)C(═O)—, (2,5-dimethoxy-phenyl)C(═O)—,(3,4-dimethoxy-phenyl)C(═O)—,

(3,5-dimethoxy-phenyl)C(═O)—, cyclopropyl-C(═O)—,

isopropyl-C(═O)—, ethyl-CO₂—, propyl-CO₂—, t-butyl-CO₂—,

2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl,

2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl,

2,4,5-trimethoxy-benzyl, 2,3,4-trimethoxy-benzyl,

3,4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl,

(4-fluoro-phenyl)ethyl,

—CH═CH₂, —CH₂—CH═CH₂, —CH═CH—CH₃, —C≡—CH, —C≡C—CH₃, and

—CH₂—C≡CH;

R⁷, R⁸, and R⁹, at each occurrence, are independently selected from

hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,

propyl, isopropyl, butyl, t-butyl, nitro,

trifluoromethyl, methoxy, ethoxy, isopropoxy,

trifluoromethoxy, phenyl,

methylC(═O)—, ethylC(═O)—, propylC(═O)—, isopropylC(═O)—,

butylC(═O)—, phenylC(═O)—,

methylCO₂—, ethylCO₂—, propylCO₂—, isopropylCO₂—,

butylCO₂—, phenylCO₂—,

dimethylamino-S(═O)—, diethylamino-S(═O)—,

dipropylamino-S(═O)—, di-isopropylamino-S(═O)—,

dibutylamino-S(═O)—, diphenylamino-S(═O)—,

dimethylamino-SO₂—, diethylamino-SO₂—, dipropylamino-SO₂—,di-isopropylamino-SO₂—, dibutylamino-SO₂—, diphenylamino-SO₂—,

dimethylamino-C(═O)—, diethylamino-C(═O)—,

dipropylamino-C(═O)—, di-isopropylamino-C(═O)—,

dibutylamino-C(═O)—, diphenylamino-C(═O)—,

2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl,2-methylphenyl, 2-trifluoromethylphenyl,

2-methoxyphenyl, 2-trifluoromethoxyphenyl,

3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,

3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl,

3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl,

3-trifluoromethylphenyl, 3-methoxyphenyl,

3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,

3-thiomethoxyphenyl,

4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,

4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl,

4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl,

4-trifluoromethylphenyl, 4-methoxyphenyl,

4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,

4-thiomethoxyphenyl,

2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,

2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,

2,3-ditrifluoromethoxyphenyl,

2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl,

2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,

2,4-ditrifluoromethoxyphenyl,

2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,

2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,

2,5-ditrifluoromethoxyphenyl,

2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,

2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,

2,6-ditrifluoromethoxyphenyl,

3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl,

3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,

3,4-ditrifluoromethoxyphenyl,

2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,

2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,

2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,

2-chloro-4-CF₃-phenyl, 2-fluoro-3-chloro-phenyl,

2-chloro-4-CF₃-phenyl, 2-chloro-4-methoxy-phenyl,

2-methoxy-4-isopropyl-phenyl, 2-CF₃-4-methoxy-phenyl,

2-methyl-4-methoxy-5-fluoro-phenyl,

2-methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl,

2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl,

methyl-C(═O)NH—, ethyl-C(═O)NH—, propyl-C(═O)NH—,

isopropyl-C(═O)NH—, butyl-C(═O)NH—, phenyl-C(═O)NH—,.

4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl, 2-furanyl,

2-thiophenyl, 2-naphthyl;

2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,

2-Me-3-Cl-phenyl, 3-NO₂-phenyl, 2-NO₂-phenyl,

2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,

2-Cl-6-F-phenyl, 2-Cl-4-(CHF₂)O-phenyl,

2,4-diMeO-6-F-phenyl, 2-CF₃-6-F-phenyl,

2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,

2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl,

2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,

2-CF₃-4-EtO-phenyl, 2-CF₃-4-iPrO-phenyl,

2-CF₃-4-Cl-phenyl, 2-CF₃-4-F-phenyl, 2-Cl-4-EtO-phenyl,

2-Cl-4-iPrO-phenyl, 2-Et-4-MeO-phenyl,

2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,

2-CH(OMe)Me-4-MeO-phenyl, 2-C(═O)Me-4-MeO-phenyl,

2-CH₂(OH)-4-MeO-phenyl, 2-CH₂(OMe)-4-MeO-phenyl,

2-CH(OH)Et-4-MeO-phenyl, 2-C(═O)Et-4-MeO-phenyl,

(Z)-2-CH═CHC₂Me-4-MeO-phenyl,

2-CH₂CH₂CO₂Me-4-MeO-phenyl,

(Z)-2-CH═CHCH₂(OH)-4-MeO-phenyl,

(E)-2-CH═CHC₂Me-4-MeO-phenyl,

(E)-2-CH═CHCH₂ (OH)-4-MeO-phenyl,

2-CH2CH₂OMe-4-MeO-phenyl,

2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl,

(2-Cl-phenyl)-CH═CH—, (3-Cl-phenyl)-CH═CH—,

(2,6-diF-phenyl)-CH═CH—, —CH₂CH═CH₂,

phenyl-CH═CH—, (2-Me-4-MeO-phenyl)-CH═CH—,

cyclohexyl, cyclopentyl, cyclohexylmethyl,

—CH₂CH₂CO₂Et, —(CH₂)₃CO₂Et, —(CH₂)₄CO₂Et,

benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,

3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl,

2-OH-benzyl, 2-CO₂Me-3-MeO-phenyl,

2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF₃-4-CN-phenyl,

3-CHO-phenyl, 3-CH₂(OH)-phenyl, 3-CH₂(OMe)-phenyl,

3-CH₂(NMe₂)-phenyl, 3-CN-4-F-phenyl,

3-CONH₂-4-F-phenyl, 2-CH₂(NH₂)-4-MeO-phenyl-,

phenyl-NH—, (4-F-phenyl)-NH—, (2,4-diCl-phenyl)-NH—,

phenyl-C(═O)NH—, benzyl-NH—, (2-Me-4-MeO-phenyl)-NH—,

(2-F-4-MeO-phenyl)-NH—, (2-Me-4-F-phenyl)-NH—,

phenyl-S—, —NMe₂, 1-pyrrolidinyl, and

—N(tosylate)₂,

provided that two of R⁷, R⁸, and R⁹, are independently selected fromhydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,isopropoxy, and trifluoromethoxy;

R^(10A) is selected from hydrogen, methyl, ethyl, benzyl and4-fluorobenzyl;

m is 1; and

n is 1 or 2.

[9] In an even more preferred embodiment of the present invention, thecompound of Formula (I) is selected from Formula (IV):

wherein:

b is a single bond, wherein the bridge hydrogens are in a cis position;

R¹ is selected from

hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl,

t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,

2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl,

2-ethylbutyl, 3-methylpentyl, 3-methylbutyl,

4-methylpentyl, 2-fluoroethyl, 2,2-difluoroethyl,

2,2,2-trifluoroethyl, 2-propenyl, 2-methyl-2-propenyl,

trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,

trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl,

4-methyl-3-pentenyl, 3,3-dichloro-2-propenyl,

trans-3-phenyl-2-propenyl, cyclopropyl, cyclobutyl,

cyclopentyl, cyclohexyl, cyclopropylmethyl,

cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,

—CH═CH₂, —CH₂—CH═CH₂, —CH═CH—CH₃, —C≡CH, —C≡C—CH₃,

and —CH₂—C≡H;

R⁷ and R⁹, at each occurrence, are independently selected from hydrogen,fluoro, methyl, trifluoromethyl, and methoxy;

R⁸ is selected from

hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,

propyl, isopropyl, butyl, t-butyl, nitro,

trifluoromethyl, methoxy, ethoxy, isopropoxy,

trifluoromethoxy, phenyl,

methylC(═O)—, ethylC(═O)—, propylC(═O)—, isopropylC(═O)—,

butylC(═O)—, phenylC(═O)—,

methylCO₂—, ethylCO₂—, propylCO₂—, isopropylCO₂—,

butylCO₂—, phenylCO₂—,

dimethylamino-S(═O)—, diethylamino-S(═O)—,

dipropylamino-S(═O)—, di-isopropylamino-S(═O)—,

dibutylamino-S(═O)—, diphenylamino-S(═O)—,

dimethylamino-SO₂—, diethylamino-SO₂—,dipropylamino-SO₂—di-isopropylamino-SO₂—, dibutylamino-SO₂—,

diphenylamino-SO₂—,

dimethylamino-C(═O)—, diethylamino-C(═O)—,

dipropylamino-C(═O)—, di-isopropylamino-C(═O)—,

dibutylamino-C(═O)—, diphenylamino-C(═O)—,

2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl,2-methylphenyl, 2-trifluoromethylphenyl,

2-methoxyphenyl, 2-trifluoromethoxyphenyl,

3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,

3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl,

3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl,

3-trifluoromethylphenyl, 3-methoxyphenyl,

3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,

3-thiomethoxyphenyl,

4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,

4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl,

4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl,

4-trifluoromethylphenyl, 4-methoxyphenyl,

4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,

4-thiomethoxyphenyl,

2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,

2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,

2,3-ditrifluoromethoxyphenyl,

2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl,

2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,

2,4-ditrifluoromethoxyphenyl,

2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,

2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,

2,5-ditrifluoromethoxyphenyl,

2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,

2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,

2,6-ditrifluoromethoxyphenyl,

3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl,

3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,

3,4-ditrifluoromethoxyphenyl,

2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,

2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,

2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,

2-chloro-4-CF₃-phenyl, 2-fluoro-3-chloro-phenyl,

2-chloro-4-CF₃-phenyl, 2-chloro-4-methoxy-phenyl,

2-methoxy-4-isopropyl-phenyl, 2-CF₃-4-methoxy-phenyl,

2-methyl-4-methoxy-5-fluoro-phenyl,

2-methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl,

2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl,

methyl-C(═O)NH—, ethyl-C(═O)NH—, propyl-C(═O)NH—, isopropyl-C(═O)NH—,butyl-C(═O)NH—, phenyl-C(═O)NH—,

4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl, 2-furanyl,

2-thiophenyl, 2-naphthyl;

2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,

2-Me-3-Cl-phenyl, 3-NO₂-phenyl, 2-NO₂-phenyl,

2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,

2-Cl-6-F-phenyl, 2-Cl-4-(CHF₂)0-phenyl,

2,4-diMeo-6-F-phenyl, 2-CF₃-6-F-phenyl,

2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,

2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl,

2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,

2-CF₃-4-EtO-phenyl, 2-CF₃-4-iPrO-phenyl,

2-CF₃-4-Cl-phenyl, 2-CF₃-4-F-phenyl, 2-Cl-4-EtO-phenyl,

2-Cl-4-iPrO-phenyl, 2-Et-4-MeO-phenyl,

2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,

2-CH(OMe)Me-4-MeO-phenyl, 2-C(═O)Me-4-MeO-phenyl,

2-CH₂(OH)-4-MeO-phenyl, 2-CH₂(OMe)-4-MeO-phenyl,

2-CH(OH)Et-4-MeO-phenyl, 2-C(═O)Et-4-MeO-phenyl,

(Z)-2-CH═CHCO₂Me-4-MeO-phenyl,

2-CH₂CH₂CO₂Me-4-MeO-phenyl,

(Z)-2-CH═CHCH₂ (OH)-4-MeO-phenyl,

(E)-2-CH═CHCO₂Me-4-MeO-phenyl,

(E)-2-CH═CHCH₂(OH)-4-MeO-phenyl,

2-CH₂CH₂OMe-4-MeO-phenyl,

2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl,

(2-Cl-phenyl)-CH═CH—, (3-Cl-phenyl)-CH═CH—,

(2,6-diF-phenyl)-CH═CH—, —CH₂CH═CH₂,

phenyl-CH═CH—, (2-Me-4-MeO-phenyl)-CH═CH—,

cyclohexyl, cyclopentyl, cyclohexylmethyl,

—CH₂CH₂CO₂Et, —(CH₂)₃CO₂Et, —(CH₂)₄CO₂Et,

benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,

3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl,

2-OH-benzyl, 2-CO₂Me-3-MeO-phenyl,

2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF₃-4-CN-phenyl,

3-CHO-phenyl, 3-CH₂(OH)-phenyl, 3-CH₂(OMe)-phenyl,

3-CH₂(NMe₂)-phenyl, 3-CN-4-F-phenyl,

3-CONH₂-4-F-phenyl, 2-CH₂(NH₂)-4-MeO-phenyl—,

phenyl-NH—, (4-F-phenyl)-NH—, (2,4-diCl-phenyl)-NH—,

phenyl-C(═O)NH—, benzyl-NH—, (2-Me-4-MeO-phenyl)-NH—,

(2-F-4-MeO-phenyl)-NH—, (2-Me-4-F-phenyl)-NH—,

phenyl-S—, —NMe₂, 1-pyrrolidinyl, and

—N(tosylate)₂;

R^(10A) is selected from hydrogen, methyl, ethyl, 4-fluorobenzyl andbenzyl; and p0 n is 1 or 2.

[10] In another preferred embodiment of the present invention,

X is —NR^(10A)—, —C(═O)NR^(10A)—, or —NR^(10A)C(═O)—;

R¹ is selected from

C₁₋₆ alkyl substituted with Z,

C₂₋₆ alkenyl substituted with Z,

C₂₋₆ alkynyl substituted with Z,

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z;

C₁₋₆ alkyl substituted with 0-2 R²,

C₂₋₆ alkenyl substituted with 0-2 R²,

C₂₋₆ alkynyl substituted with 0-2 R²,

aryl substituted with 0-2 R², and

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with 0-2 R²;

Z is selected from H,

—CH(OH)R²,

—C(ethylenedioxy)R²,

—OR²,

—SR²,

—NR²R³,

—C(O)R²,

—C(O)NR²R³,

—NR3C(O)R²,

—C(O)OR²,

—OC(O)R²,

—CH(═NR⁴)NR²R³,

—NHC(═NR⁴)NR²R³,

—S(O)R²,

—S(O)₂R²,

—S(O)₂NR²R³, and —NR³S(O)₂R²;

R², at each occurrence, is independently selected from

—C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

aryl substituted with 0-5 R⁴²;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and

C₁ ₁₋₄ alkoxy;

alternatively, R² and R³ join to form a 5- or 6-membered ring optionallysubstituted with —O— or —N(R⁴)—;

R⁴, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R⁵ is H, methyl, ethyl, propyl, or butyl;

R^(6a) is selected from

H, —OH, —NR⁴⁶R⁴⁷, —CF₃,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₃₋₆ cycloalkyl, and

aryl substituted with 0-3 R⁴⁴;

R^(6b) is H;

R⁷, R⁸, and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹² _(,) C(O)NR¹²R¹³, NR¹⁴C(O)R¹²,C(O)OR¹², OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³,S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴,S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R^(10A) is selected from H,

C₁₋₆ alkyl substituted with 0-1 R^(10B),

C₂₋₆ alkenyl substituted with 0-1 R^(10B),

C₂₋₆ alkynyl substituted with 0-1 R^(10B), and

C₁₋₆ alkoxy;

R^(10B) is selected from

C₁₋₄ alkoxy,

C₃₋₆ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

phenyl substituted with 0-3 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴;

R¹¹ is selected from

H, halo, —CF₃, —CN, —NO₂,

C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy,C₃₋₁₀ cycloalkyl,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, CO)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S()₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²;

R¹², at each occurrence, is independently selected from

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

R¹⁴, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, methyl, ethyl, and propyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷,

C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₃₋₅ cycloalkyl, C₁₋₃ haloalkyl,C₁₋₃ haloalkyl-oxy-, C₁₋₃ alkyloxy-, C₁₋₃ alkylthio-, C₁₋₃ alkyl-C(═O)—,and C₁₋₃ alkyl-C(═O)NH—;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O,

C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴², and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN,CH(═NH)NH₂, NHC(═NH)NH₂,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴⁴, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H,

halo, —OH, NR⁴⁶R⁴⁷, C₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂,

C₁₋₄ alkyl, and C₁₋₄ alkoxy;

R⁴⁵ is C₁₋₄ alkyl;

R⁴⁶, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R⁴⁷, at each occurrence, is independently selected from H,

C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl),

—SO2(phenyl), —C(═O)O(C₁₋₄ alkyl), —C(═O)( C₁₋₄ alkyl),

and —C(═O)H;

R⁴⁸, at each occurrence, is independently selected from H,

C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl),

—C(═O)(C₁₋₄ alkyl), and —C(═O)H;

k is 1 or 2;

m is 0, 1, or 2; and

n is 1 or 2.

[11] In a further preferred embodiment of the present invention,

X is —NR^(10A)—;

R¹ is selected from

C₂₋₅ alkyl substituted with Z,

C₂₋₅ alkenyl substituted with Z,

C₂₋₅ alkynyl substituted with Z,

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z;

C₁₋₅ alkyl substituted with 0-2 R²,

C₂₋₅ alkenyl substituted with 0-2 R², and

C₂₋₅ alkynyl substituted with 0-2 R²;

Z is selected from H,

CH(OH)R²,

—C(ethylenedioxy)R²,

—OR²,

—SR²,

—NR²R³,

—C(O)R²,

—C(O)NR²R³,

—NR³C(O)R²,

—C(O)OR²,

—OC(O)R²,

—CH(═NR⁴)NR²R³,

—NHC(═NR⁴)NR²R³,

—S(O)R²,

—S(O)₂R²,

—S(O)₂NR²R³, and —NR³S(O)₂R²;

R², at each occurrence, is independently selected from

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

aryl substituted with 0-5 R⁴²;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and

C₁₋₄ alkoxy;

alternatively, R² and R³ join to form a 5- or 6-membered ring optionallysubstituted with —O— or —N(R⁴)—;

R⁴, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R⁵ is H, methyl, or ethyl;

R^(6a) is selected from

H, —OH, —NR⁴⁶R⁴⁷, —CF₃,

C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, andC₃₋₆ cycloalkyl;

R^(6b) is H;

R⁷, R⁸, and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —OCH₃, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₆ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₁₋₄ alkyl substituted with 0-2 R¹¹,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹² _(,) C(O)NR¹²R¹³, NR¹⁴C(O)R¹²,C(O)OR¹², OC(O)R¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)₂NR¹²R¹³, NR¹⁴S(O)₂R¹², NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;

R^(10A) is selected from H,

C₁₋₆ alkyl substituted with 0-1 R^(10B),

C₂₋₆ alkenyl substituted with 0-1 R^(10B),

C₂₋₆ alkynyl substituted with 0-1 R^(10B), and

C₁₋₆ alkoxy;

R^(10B) is selected from

C₁₋₄ alkoxy,

C₃₋₆ cycloalkyl,

C₃₋₆ carbocyclic residue substituted with 0-3 R³³,

phenyl substituted with 0-3 R³³, and

5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴;

R¹¹is selected from

H, halo, —CF₃, —OCF₃, —OH, —OCH₃, —CN, —NO₂, —NR⁴⁶R⁴⁷,

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₆ alkoxy,(C₁₋₄ haloalkyl)oxy,

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

aryl substituted with 0-5 R³³,

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹² _(,) C(O)NR¹²R¹³, NR¹⁴C(O)R¹²,C(O)OR¹², OC(O)R¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)₂NR¹²R¹³, and NR¹⁴S(O)₂R¹²;

R¹² at each occurrence, is independently selected from

C₁₋₄ alkyl,

C₂₋₄ alkenyl,

C₂₋₄ alkynyl,

C₃₋₆ cycloalkyl,

phenyl substituted with 0-5 R³³;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹;

R¹³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

R¹⁴, at each occurrence, is independently selected from H and C₁₋₄alkyl;

R³¹, at each occurrence, is independently selected from

H, OH, halo, CF₃, methyl, and ethyl;

R³³, at each occurrence, is independently selected from

H, OH, halo, CN, NO₂, CF₃, methyl, and ethyl;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O,

C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴², and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN,CH(═NH)NH₂, NHC(═NH)NH₂,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴⁴, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H, halo, —OH,NR⁴⁶R⁴⁷, C₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy;

R⁴⁵ is C₁₋₄ alkyl;

R⁴⁶, at each occurrence, is independently selected from H

and C₁₋₃ alkyl;

R⁴⁷, at each occurrence, is independently selected from H,

C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl),

—SO2(phenyl), —C(═O)O(C₁₋₄ alkyl), —C(═O)( C₁₋₄ alkyl)

and —C(═O)H;

R⁴⁸, at each occurrence, is independently selected from H,

C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl),

—C(═O)( C₁₋₄ alkyl), and —C(═O)H;

k is 1 or 2;

m is 0, 1, 2; and

n is 1 or 2.

[12] In more preferred embodiment of the present invention,

X is —NR^(10A)—;

R¹ is selected from

C₂₋₄ alkyl substituted with Z,

C₂₋₄ alkenyl substituted with Z,

C₂₋₄ alkynyl substituted with Z,

C₃₋₆ cycloalkyl substituted with Z,

aryl substituted with Z,

5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with Z;

C₂₋₄ alkyl substituted with 0-2 R², and

C₂₋₄ alkenyl substituted with 0-2 R²;

Z is selected from H,

—CH(OH)R²,

—C(ethylenedioxy)R²,

—OR²,

—SR²,

—NR²R³,

—C(O)R²,

—C(O)NR²R³,

—NR³C(O)R²,

—C( O)OR²,

—S(O)R²,

—S(O)₂R²,

—S(O)₂NR²R³, and —NR³S(O)₂R²;

R², at each occurrence, is independently selected from

phenyl substituted with 0-5 R⁴²;

C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹;

R³, at each occurrence, is independently selected from

H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and

C₁₋₄ alkoxy;

alternatively, R² and R³ join to form a 5- or 6-membered ring optionallysubstituted with —O——or —N(R⁴)—;

R⁴, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R⁵ is H;

R^(6a) is selected from H, —OH, —CF₃, methyl, ethyl, propyl, butyl,methoxy, and, ethoxy;

R^(6b) is H;

R⁷, R⁸, and R⁹, at each occurrence, are independently selected from

H, halo, —CF₃, —OCF₃, —OH, —OCH₃, —CN, —NO₂,

C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, (C₁₋₃ haloalkyl)oxy, and

C₁₋₄ alkyl substituted with 0-2 R¹¹;

R^(10A) is selected from H, C₁₋₆ alkyl, C₁₋₄ alkoxy, and

C₁₋₂ alkyl substituted with 0-1 R^(10B);

R^(10B) is C₃₋₆ cycloalkyl or

phenyl substituted with 0-3 R³³;

R¹¹is selected from

H, halo, —CF₃, —OCF₃, —OH, —OCH₃, —CN, —NO₂,

C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and (C₁₋₃ haloalkyl)oxy;

R³³, at each occurrence, is independently selected from

H, OH, halo, CF₃, and methyl;

R⁴¹, at each occurrence, is independently selected from

H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O,

C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴², and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴², at each occurrence, is independently selected from

H, CF₃, halo, OH, C₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

C₁₋₄ alkyl substituted with 0-1 R⁴³,

aryl substituted with 0-3 R⁴⁴, and

5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴;

R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

phenyl, or pyridyl, each substituted with 0-3 R⁴⁴;

R⁴⁴, at each occurrence, is independently selected from H, halo, —OH,NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂,

methyl, ethyl, propyl, butyl, methoxy, ethoxy,

propoxy, and butoxy;

R⁴⁵ is methyl, ethyl, propyl, or butyl;

R⁴⁶, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R⁴⁷, at each occurrence, is independently selected from

H, methyl, ethyl, n-propyl, 1-propyl, n-butyl,

i-butyl, —C(═O)NH(methyl), —C(═O)NH(ethyl),

—SO₂(methyl), —SO₂(ethyl), —SO₂(phenyl),

—C(═O)O(methyl), —C(═O)O(ethyl), —C(═O)(methyl),

—C(═O)(ethyl), and —C(═O)H;

R⁴⁸, at each occurrence, is independently selected from

H, methyl, ethyl, n-propyl, i-propyl, —C(═O)NH(methyl), —C(═O)NH(ethyl),—C(═O)O(methyl), —C(═O)O(ethyl), —C(═O)(methyl), —C(═O)(ethyl), and—C(═O)H;

k is 1;

m is 0, 1, or 2; and

n is 1 or 2.

[13] In an even more preferred embodiment of the present invention,

X is —NH—;

R¹ is selected from

ethyl substituted with Z,

propyl substituted with Z,

butyl substituted with Z,

propenyl substituted with Z,

butenyl substituted with Z,

ethyl substituted with R²,

propyl substituted with R²,

butyl substituted with R²,

propenyl substituted with R², and

butenyl substituted with R²;

Z is selected from H,

—CH(OH)R²,

—OR²,

—SR²,

—NR²R³,

—C(O)R²,

—C(O)NR²R³,

—NR³C(O)R²,

—C(O)OR²,

—S(O)R²,

—S(O)₂R²,

—S(O)₂NR²R³, and —NR³S(O)₂R²;

R², at each occurrence, is independently selected from

phenyl substituted with 0-3 R⁴²;

naphthyl substituted with 0-3 R⁴²;

cyclopropyl substituted with 0-3 R⁴¹;

cyclobutyl substituted with 0-3 R⁴¹;

cyclopentyl substituted with 0-3 R⁴¹;

cyclohexyl substituted with 0-3 R⁴¹;

pyridyl substituted with 0-3 R⁴¹;

indolyl substituted with 0-3 R⁴¹;

indolinyl substituted with 0-3 R⁴¹;

benzimidazolyl substituted with 0-3 R⁴¹;

benzotriazolyl substituted with 0-3 R⁴¹;

benzothienyl substituted with 0-3 R⁴¹;

benzofuranyl substituted with 0-3 R⁴¹;

phthalimid-1-yl substituted with 0-3 R⁴¹;

inden-2-yl substituted with 0-3 R⁴¹;

2,3-dihydro-1H-inden-2-yl substituted with 0-3 R⁴¹;

indazolyl substituted with 0-3 R⁴¹;

tetrahydroquinolinyl substituted with 0-3 R⁴¹; and

tetrahydro-isoquinolinyl substituted with 0-3 R⁴¹;

R³, at each occurrence, is independently selected from

H, methyl, and ethyl;

R⁵ is H;

R^(6a) is selected from H, —OH, methyl, and methoxy;

R^(6b) is H;

R⁷, R⁸, and R⁹, at each occurrence, are independently selected from H,F, Cl, methyl, ethyl, methoxy, —CF₃, and —OCF₃;

R⁴¹, at each occurrence, is independently selected from

H, F, Cl, Br, OH, CF₃, NO₂, CN, ═O, methyl, ethyl, propyl, butyl,methoxy, and ethoxy;

R⁴², at each occurrence, is independently selected from

H, F, Cl, Br, OH, CF₃, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, ═O, methyl,ethyl, propyl, butyl, methoxy, and ethoxy;

R⁴⁵ is methyl, ethyl, propyl, or butyl;

R⁴⁶, at each occurrence, is independently selected from H,

methyl, ethyl, propyl, and butyl;

R⁴⁷, at each occurrence, is independently selected from

H, methyl, ethyl, n-propyl, i-propyl, n-butyl,

i-butyl, —C(═O)NH(methyl), —C(═O)NH(ethyl),

—SO₂(methyl), —SO₂(ethyl), —SO₂(phenyl),

—C(═O)O(methyl),—C(═O)O(ethyl), —C(═O)(methyl),

—C(═O)(ethyl), and —C(═O)H;

R⁴⁸, at each occurrence, is independently selected from

H, methyl, ethyl, n-propyl, i-propyl, —C(═O)NH(methyl), —C(═O)NH(ethyl),—C(═O)O(methyl), —C(═O)O(ethyl), —C(═O)(methyl), —C(═O)(ethyl), and—C(═O)H;

k is 1;

m is 0, 1, or 2; and

n is 1 or 2.

[14] In another even more preferred embodiment of the present invention,the compound of Formula (I) is selected from Formula (I-a):

wherein:

b is a single bond or a double bond;

X is —NR^(10A)—;

R¹ is selected from

—(CH₂)₃C(═O)(4-fluoro-phenyl),

—(CH₂)₃C(═O)(4-bromo-phenyl),

—(CH₂)₃C(═O)(4-methyl-phenyl),

—(CH₂)₃C(═O)(4-methoxy-phenyl),

—(CH₂)₃C(═O)(4-(3,4-dichloro-phenyl)phenyl),

—(CH₂)₃C(═O)(3-methyl-4-fluoro-phenyl),

—(CH₂)₃C(═O)(2,3-dimethoxy-phenyl),

—(CH₂)₃C(═O)(phenyl),

—(CH₂)₃C(═O)(4-chloro-phenyl),

—(CH₂)₃C(═O)(3-methyl-phenyl),

—(CH₂)₃C(═O)(4-t-butyl-phenyl),

—(CH₂)₃C(═O)(3,4-difluoro-phenyl),

—(CH₂)₃C(═O)(2-methoxy-5-fluoro-phenyl),

—(CH₂)₃C(═O)(4-fluoro-1-naphthyl),

—(CH₂)₃C(═O)(benzyl),

—(CH₂)₃ C(═O)(4-pyridyl),

—(CH₂)₃C(═O)(3-pyridyl),

—(CH₂)₃CH(OH)(4-fluoro-phenyl),

—(CH₂)₃CH(OH)(4-pyridyl),

—(CH₂)₃CH(OH)(2,3-dimethoxy-phenyl),

—(CH₂)₃S(3-fluoro-phenyl),

—(CH₂)₃S(4-fluoro-phenyl),

—(CH₂)₃S(═O)(4-fluoro-phenyl),

—(CH₂)₃ SO₂(3-fluoro-phenyl),

—(CH₂)₃ SO₂(4-fluoro-phenyl),

—(CH₂)₃O(4-fluoro-phenyl),

—(CH₂)₃O(phenyl),

—(CH₂)₃O(3-pyridyl),

—(CH₂)₃O(4-pyridyl),

—(CH₂)₃O(2-NH₂-phenyl),

—(CH₂)₃O(2-NH₂-5-F-phenyl),

—(CH₂)₃O(²-NH₂-4-F-phenyl),

—(CH₂)₃O(2-NH₂-3-F-phenyl),

—(CH₂)₃O(2-NH₂-4-Cl-phenyl),

—(CH₂)₃O(²-NH₂-4-OH-phenyl),

—(CH₂)₃O(2-NH₂-4-Br-phenyl),

—(CH₂)₃O(2-NHC(═O)Me-4-F-phenyl),

—(CH₂)₃O(2-NHC(═O)Me-phenyl)

—(CH₂)₃NH(4-fluoro-phenyl),

—(CH₂)₃N(methyl)(4-fluoro-phenyl),

—(CH₂)₃C₂(ethyl),

—(CH₂)₃C(═O)N(methyl)(methoxy),

—(CH₂)₃C(═O)NH(4-fluoro-phenyl) ,

—(CH₂)₂NHC(═O)(phenyl),

—(CH₂)₂NMeC(═O)(phenyl),

—(CH₂)₂NHC(═O)(2-fluoro-phenyl),

—(CH₂)₂NMeC(═O)(2-fluoro-phenyl),

—(CH₂)₂NHC(═O)(4-fluoro-phenyl),

—(CH₂)₂NMeC(═O)(4-fluoro-phenyl),

—(CH₂)₂NHC(═O)(2,4-difluoro-phenyl),

—(CH₂)₂NMeC(═O)(2,4-difluoro-phenyl),

—(CH₂)₃(3-indolyl),

—(CH₂)₃(1-methyl-3-indolyl),

—(CH₂)₃(1-indolyl),

—(CH₂)₃(1-indolinyl)

—(CH₂)₃(1-benzimidazolyl)

—(CH₂)₃(1H-1,2,3-benzotriazol-1-yl),

—(CH₂)₃(1H-1,2,3-benzotriazol-2-yl),

—(CH₂)₂(1H-1,2,3-benzotriazol-1-yl),

—(CH₂)₂(1H-1,2,3-benzotriazol-2-yl),

—(CH₂)₃(3,4 dihydro-1(2H)-quinolinyl),

—(CH₂)₂C(═O)(4-fluoro-phenyl),

—(CH₂)₂C(═O)NH(4-fluoro-phenyl),

—CH₂CH₂(3-indolyl),

—CH₂CH₂(1-phthalimidyl),

—(CH₂)₄C(═O)N(methyl)(methoxy),

—(CH₂)₄CO₂(ethyl),

—(CH₂)₄C(═O)(phenyl),

—(CH₂)₄(cyclohexyl),

—(CH₂)₃CH(phenyl)₂,

—CH₂CH₂CH═C(phenyl)₂,

—CH₂CH₂CH═CMe(4-F-phenyl),

—CH₂)₃CH (4-fluoro-phenyl)₂,

—(CH₂CH₂CH═C(4-fluoro-phenyl)₂,

—(CH₂)₂ (2,3-dihydro-1H-inden-2-yl) ,

—(CH₂)₃C(═O)(2-NH₂-phenyl),

—(CH₂)₃C(═O)(2-NH₂-5-F-phenyl),

—(CH₂)₃C(═O)(2-NH₂-4-F-phenyl),

—(CH₂)₃C(═O)(2-NH₂-3-F-phenyl),

—(CH₂)₃C(═O)(2-NH₂-4-Cl-phenyl),

—(CH₂)₃C(═O)(2-NH₂-4-OH-phenyl),

—(CH₂)₃C(═O)(2-NH₂-4-Br-phenyl),

—(CH₂)₃(1H-indazol-3-yl),

—(CH₂)₃(5-F-1H-indazol-3-yl),

—(CH₂)₃(7-F-1H-indazol-3-yl),

—(CH₂)₃(6-Cl-1H-indazol-3-yl),

—(CH₂)₃(6-Br-1H-indazol-3-yl),

—(CH₂)₃C(═O)(2-NHMe-phenyl),

—(CH₂)₃(1-benzothien-3-yl),

—(CH₂)₃(6-F-1H-indol-1-yl)

—(CH₂)₃(5-F-1H-indol-1-yl),

—(CH₂)₃(6-F-2,3-dihydro-1H-indol-1-yl),

—(CH₂)₃(5-F-2,3-dihydro-1H-indol-1-yl),

—(CH₂)₃(6-F-1H-indol-3-yl),

—(CH₂)₃ (5-F-1H-indol-3-yl),

—(CH₂ )₃(5-F-1H-indol-3-yl),

—(CH₂)₃(5-F-1H-indol-3-yl),

—(CH₂)₃ (9H-purin-9-yl),

—(CH₂)₃(7H-purin-7-yl),

—(CH₂)₃(6-F-1H-indazol-3-yl),

—(CH₂)₃C(═O)(2-NHSO₂Me-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHC(═O)Me-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHC(═O)Me-phenyl),

—(CH₂)₃C(═O)(2-NHCO₂Et-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHC(═O)NHEt-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHCHO-4-F-phenyl),

—(CH₂)₃C(═O)(2-OH-4-F-phenyl),

—(CH₂)₃C(═O)(2-MeS-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHSO₂Me-4-F-phenyl),

—(CH₂)₂C(Me)CO₂Me,

—(CH₂)₂C(Me)CH(OH)(4-F-phenyl)₂,

—(CH₂)₂C(Me)CH(OH)(4-Cl-phenyl)₂,

—(CH₂)₂C(Me)C(═O)(4-F-phenyl),

—(CH₂)₂C(Me)C(═O)(2-MeO-4-F-phenyl),

—(CH₂)₂C(Me)C(═O)(3-Me-4-F-phenyl),

—(CH₂)₂C(Me)C(═O)(2-Me-phenyl),

—(CH₂)₂C(Me)C(═O)phenyl,

R⁷, R⁸, and R⁹, at each occurrence, are independently selected from

hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,

propyl, isopropyl, butyl, t-butyl, nitro,

trifluoromethyl, methoxy, ethoxy, isopropoxy,

trifluoromethoxy, phenyl, benzyl,

HC(═O)—, methylC(═O)—, ethylC(═O)—, propylC(═O)—,

isopropylC(═O)—, n-butylC(═O)—, isobutylC(═O)—,

secbutylC(═O)—, tertbutylC(═O)—, phenylC(═O)—,

methylC(═O)NH—, ethylC(═O)NH —, propylC(═O)NH—,

isopropylC(═O)NH—, n-butylC(═O)NH—, isobutylC(═O)NH—,

secbutylC(═O)NH—, tertbutylC(═O)NH—, phenylC(═O)NH—,

methylamino-, ethylamino-, propylamino-, isopropylamino-,

n-butylamnino-, isobutylamino-, secbutylamino-,

tertbutylamino-, phenylamino-,

provided that two of substituents R⁷, R⁸ and R⁹, are independentlyselected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy,ethoxy, isopropoxy, and trifluoromethoxy;

R^(10A) is selected from hydrogen, methyl, ethyl, propyl, isopropyl,butyl, benzyl, 2-chlorobenzyl, 2-fluorobenzyl, 2-bromobenzyl,2-methylbenzyl, 2-trifluoromethylbenzyl, 2-methoxybenzyl,2-trifluoromethoxybenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-bromobenzyl,3-methylbenzyl, 3-trifluoromethylbenzyl, 3-methoxybenzyl,3-trifluoromethoxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl,4-methylbenzyl, 4-trifluoromethylbenzyl, 4-methoxybenzyl, and4-trifluoromethoxybenzyl;

k is 1 or 2;

m is 1 or 2; and

n is 1 or 2.

[15] In another even more preferred embodiment of the present invention,the compound of Formula (I) is selected from Formula (IV-a):

wherein:

b is a single bond, wherein the bridge hydrogens are in a cis position;

R¹ is selected from

—(CH₂)₃C(═O)(4-fluoro-phenyl),

—(CH₂)₃C(═O)(4-bromo-phenyl),

—(CH₂)₃C(═O)(4-methyl-phenyl),

—(CH₂)₃C(═O)(4-methoxy-phenyl),

—(CH₂)₃C(═O)(4-(3,4-dichloro-phenyl)phenyl),

—(CH₂)₃C(═O)(3-methyl-4-fluoro-phenyl),

—(CH₂)₃C(═O)(2,3-dimethoxy-phenyl),

—(CH₂)₃C(═O)(phenyl),

—(CH₂)₃C(═O)(4-chloro-phenyl),

—(CH₂)₃C(═O)(3-methyl-phenyl),

—(CH₂)₃C(═O)(4-t-butyl-phenyl),

—(CH₂)₃C(═O)(3,4-difluoro-phenyl),

—(CH₂)₃C(═O)(2-methoxy-5-fluoro-phenyl),

—(CH₂)₃C(═O)(4-fluoro-1-naphthyl),

—(CH₂)₃C(═O)(benzyl),

—(CH₂)₃C(═O)(4-pyridyl),

—(CH₂)₃C(═O)(3-pyridyl),

—(CH₂)₃CH(OH)(4-fluoro-phenyl),

—(CH₂)₃CH(OH)(4-pyridyl),

—(CH₂)₃CH(OH)(2,3-dimethoxy-phenyl),

—(CH₂)₃S(3-fluoro-phenyl),

—(CH₂)₃S(4-fluoro-phenyl),

—(CH₂)₃S(═O)(4-fluoro-phenyl),

—(CH₂)₃SO₂(3-fluoro-phenyl),

—(CH₂)₃SO₂(4-fluoro-phenyl),

—(CH₂)₃O(4-fluoro-phenyl),

—(CH₂)₃O(phenyl)

—(CH₂)₃NH(4-fluoro-phenyl),

—(CH₂)₃N(methyl)(4-fluoro-phenyl),

—(CH₂)₃CO₂(ethyl),

—(CH₂)₃C(═O)N(methyl)(methoxy),

—(CH₂)₃C(═O)NH(4-fluoro-phenyl),

—(CH₂)₂NHC(═O)(phenyl),

—(CH₂)₂NMeC(═O)(phenyl),

—(CH₂)₂NHC(═O)(2-fluoro-phenyl),

—(CH₂)₂NMeC(═O)(2-fluoro-phenyl) ,

—(CH₂)₂NHC(═O)(4-fluoro-phenyl),

—(CH₂)₂NMeC(═O)(4-fluoro-phenyl)

—(CH₂)₂NHC(═O)(2,4-difluoro-phenyl),

—(CH₂)₂NMeC(═O)(2,4-difluoro-phenyl),

—(CH₂)₃(3-indolyl),

—(CH₂)₃(1-methyl-3-indolyl)

—(CH₂)₃(1-indolyl),

—(CH₂)₃(1-indolinyl),

—(CH₂)₃(1-benzimidazolyl),

—(CH₂)₃(1H-1,2,3-benzotriazol-1-yl),

—(CH₂)₃(1H-1,2,3-benzotriazol-2-yl),

—(CH₂)₂(1H-1,2,3-benzotriazol-1-yl)

—(CH₂)₂(1H-1,2,3-benzotriazol-2-yl),

—(CH₂)₃(3,4 dihydro-1(2H)-quinolinyl),

—(CH₂)₂C(═O)(4-fluoro-phenyl),

—(CH₂)₂C(═O)NH(4-fluoro-phenyl)

—CH₂CH₂(3-indolyl),

—CH₂CH₂(1-phthalimidyl) ,

—(CH₂)₄C(═O)N(methyl)(methoxy),

—(CH₂)₄C₂(ethyl),

—(CH₂)₄C(═O)(phenyl),

—(CH₂)₄(cyclohexyl),

—(CH₂)₃CH(phenyl)₂,

—CH₂CH₂CH═C(phenyl)₂,

—CH₂CH₂CH═CMe(4-F-phenyl),

—(CH₂)₃CH(4-fuoro-phenyl)₂,

—CH₂CH₂CH═C(4-fluoro-phenyl)₂,

—(CH₂)₂(2,3-dihydro-1H-inden-2-yl),

—(CH₂)₃C(═O)(2-NH₂-phenyl),

—(CH₂)₃C(═O)(2-NH₂-5-F-phenyl),

—(CH₂)₃C(═O)(2-NH₂-4-F-phenyl),

—(CH₂)₃C(═O)(2-NH₂-3-F-phenyl),

—(CH₂)₃C(═O)(2-NH₂-4-Cl-phenyl),

—(CH₂)₃C(═O)(2-NH₂-4-OH-phenyl),

—(CH₂)₃C(═O)(2-NH₂-4-Br-phenyl),

—(CH₂)₃(1H-indazol-3-yl),

—(CH₂)₃(5-F-1H-indazol-3-yl),

—(CH₂)₃(7-F-1H-indazol-3-yl),

—(CH₂)₃(6-Cl-1H-indazol-3-yl) ,

—(CH₂)₃(6-Br-1H-indazol-3-yl),

—(CH₂)₃C(═O)(2-NHMe-phenyl),

—(CH₂)₃(1-benzothien-3-yl),

—(CH₂)₃(6-F-1H-indol-1-yl),

—(CH₂)₃(5-F-1H-indol-1-yl) ,

—(CH₂)₃(6-F-2,3-dihydro-1H-indol-1-yl),

—(CH₂)₃(5-F-2,3-dihydro-1H-indol-1-yl),

—(CH₂)₃(6-F-1H-indol-3-yl),

—(CH₂)₃(5-F-1H-indol-3-yl),

—(CH₂)₃(5-F-1H-indol-3-yl),

—(CH₂)₃(9H-purin-9-yl),

—(CH₂)₃(7H-purin-7-yl),

—(CH₂)₃(6-F-1H-indazol-3-yl),

—(CH₂)₃C(═O)(2-NHSO₂Me-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHC(═O)Me-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHC(═O)Me-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHCO₂Et-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHC(═O)NHEt-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHCHO-4-F-phenyl),

—(CH₂)₃(═O)(2-OH-4-F-phenyl),

—(CH₂)₃C(═O)(2-MeS-4-F-phenyl),

—(CH₂)₃C(═O)(2-NHSO₂Me-4-F-phenyl),

—(CH₂)₂C(Me)CO₂Me,

—(H₂)₂C(Me)CH(OH)(4-F-phenyl)₂,

—(CH₂)₂C(Me)CH(OH)(4-Cl-phenyl)₂,

—(CH₂)₂C(Me)C(═O)(4-F-phenyl)₂,

—(CH₂)₂C(Me)C(═O)(2-MeO-4-F-phenyl),

—(CH₂)₂C(Me)C(═O)(3-Me-4-F-phenyl),

—(CH₂)₂C(Me)C(═O)(2-Me-phenyl),

—(CH₂)₂C(Me)C(═O)phenyl,

R⁷, R⁸, and R⁹, at each occurrence, are independently selected fromhydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,isopropoxy, trifluoromethoxy, methylC(═O)—, ethylC(═O)—, propylC(═O)—,isopropylC(═O)—, methylC(═O)NH—, ethylC(═O)NH—, propylC(═O)NH—,isopropylC(═O)NH, methylamino-, ethylamino-, propylamino-, andisopropylamino-,

provided that two of substituents R⁷, R⁸, and R⁹, are independentlyselected from hydrogen, fluoro, chloro, methyl, trifluoromethyl,methoxy, and trifluoromethoxy;

R^(10A) is selected from hydrogen, methyl, ethyl, propyl, isopropyl,butyl, benzyl, 2-chlorobenzyl, 2-fluorobenzyl, 2-bromobenzyl,2-methylbenzyl, 2-trifluoromethylbenzyl, 2-methoxybenzyl,2-trifluoromethoxybenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-bromobenzyl,3-methylbenzyl, 3-trifluoromethylbenzyl, 3-methoxybenzyl,3-trifluoromethoxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl,4-methylbenzyl, 4-trifluoromethylbenzyl, 4-methoxybenzyl, and4-trifluoromethoxybenzyl;

m is 1 or 2; and

n is 1 or 2.

In an even further more preferred embodiment of the present invention,are compounds of Formula (I) selected from Table 1.

In a second embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier.

In a third embodiment, the present invention provides a method for thetreatment a central nervous system disorder comprising administering toa host in need of such treatment a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,wherein the compound is a 5HT2a antagonist or a 5HT2c agonist.

In a preferred embodiment the compound is a 5HT2a antagonist.

In another preferred embodiment the compound is a 5HT2c agonist.

In a more preferred embodiment the present invention provides a methodfor the treatment central nervous system disorders including obesity,anxiety, depression, psychosis, schizophrenia, sleep disorders, sexualdisorders, migraine, conditions associated with cephalic pain, socialphobias, and gastrointestinal disorders such as dysfunction of thegastrointestinal tract motility comprising administering to a host inneed of such treatment a therapeutically effective amount of a compoundof Formula (I).

In a further preferred embodiment the central nervous system disordercomprises obesity.

In another further preferred embodiment the central nervous systemdisorder comprises schizophrenia.

In another further preferred embodiment the central nervous systemdisorder comprises depression.

In another further preferred embodiment the central nervous systemdisorder comprises anxiety.

In a fourth embodiment the present invention provides novel compounds ofFormula (I) or pharmaceutically acceptable salt forms thereof for use intherapy.

In a fifth embodiment the present invention provides the use of novelcompounds of Formula (I) or pharmaceutically acceptable salt formsthereof for the manufacture of a medicament for the treatment of centralnervous system disorders including obesity, anxiety, depression,psychosis, schizophrenia, sleep disorders, sexual disorders, migraine,conditions associated with cephalic pain, social phobias, andgastrointestinal disorders.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The numbering of the tetracyclic ring-system present in the compounds ofFormula (I), as defined by nomenclature known to one skilled in the art,is shown for two examples in Formula (I′), when k is 1, m is 1, and n is1; and in Formula (I″), when k is 1, m is 1, and n is 2:

The tetracyclic ring-system present in compounds of Formula (I) occur as“cis” or “trans” isomers when the carbon-carbon bond b in Formula (I) isa single bond. As such, the terms “cis” and “trans”, in conjunction withthe tetracyclic ring structure, refer to the configuration of hydrogenatoms on carbon atoms 7a and 11a in Formula (I′) or, for example, oncarbon atoms 8a and 12a in Formula (I″), above. When both hydrogens areon the same side of the mean plane determined by the octahydrotetracyclic moiety then the configuration is designated “cis”, if not,the configuration is designated “trans”. It is understood that the aboveexample is for demonstrative puproses only and not intended to limit thescope of the tetracyclic ring-system present in compounds of Formula(I). As such, it is understood that one skilled in the art of organicchemistry can apply the above numbering system to other values of k, m,and n in the scope of compounds of Formula (I) to deterine theappropriate numbering. Additional Examples of the numbering of thetetracyclic ring-system are further provided below in the syntheticExamples. Lastly, it is understood that the use of “cis” or “trans” inthe identification of the tetracyclic ring-system is not meant toconstrue the configuration of any other cis or trans geometric isomer inthe molecule, for example, cis or trans butene.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R²) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R², then saidgroup may optionally be substituted with up to two R² groups and R² ateach occurrence is selected independently from the definition of R².Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl,2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither a straight or branched configuration having the specified numberof carbon atoms and one or more unsaturated carbon-carbon bonds whichmay occur in any stable point along the chain. Examples of alkenylinclude, but are not limited to, ethenyl, 1-propenyl, 2-propenyl,2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl,4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or morecarbon-carbon triple bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and thelike.

“Cycloalkyl” is intended to include saturated ring groups, having thespecified number of carbon atoms. For example, “C₃-C₆ cycloalkyl”denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.Examples of alkoxy include, but are not limited to, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, ands-pentoxy. Similarly, “alkylthio” is represents an alkyl group asdefined above with the indicated number of carbon atoms attached througha sulpher bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen (for example—C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,heptafluoropropyl, and heptachloropropyl.

As used herein, “carbocycle” is intended to mean any stable 3- to7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic ring” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 14-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and 1, 2, 3 or 4 heteroatoms independently selected from the groupconsisting of N, O and S and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.Preferred heterocycles include, but are not limited to, pyridinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl,benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl,isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,imidazolopyridinyl, and pyrazolopyridinyl. Preferred 5 to 6 memberedheterocycles include, but are not limited to, pyridinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, andoxazolidinyl. Also included are fused ring and spiro compoundscontaining, for example, the above heterocycles.

As used herein, the term “bicyclic heterocyclic ring system” is intendedto mean a stable 9- to 10-membered bicyclic heterocyclic ring formedfrom the substituent R¹²R¹³, which is partially unsaturated orunsaturated (aromatic), and which consists of carbon atoms, a nitrogenatom, and 1 or 2 additional heteroatoms independently selected from thegroup consisting of N, O and S. The additional nitrogen or sulfurheteroatoms may optionally be oxidized. The heterocyclic ring isattached to its pendant group by the nitrogen atom of the group NR¹²R¹³and for which results in a stable structure. The heterocyclic ringsdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. If specifically noted, a nitrogen inthe heterocycle may optionally be quaternized. It is preferred that whenthe total number of S and O atoms in the heterocycle exceeds 1, thenthese heteroatoms are not adjacent to one another. It is preferred thatthe total number of S and O atoms in the heterocycle is not more than 1.The term “bicyclic heterocyclic ring system” is intended to be a subsetof the term “heterocyclic ring system”. Preferred examples of a 9- to10- membered bicyclic heterocyclic ring system are benzimidazolyl,benzimidazolinyl, benzoxazolinyl, dihydrobenzthiazolyl,dihydrodioxobenzthiazolyl, benzisoxazolinyl, 1H-indazolyl, indolyl,indolinyl, isoindolinyl, tetrahydro-isoquinolinyl,tetrahydro-quinolinyl, and benzotriazolyl.

Additionally, a subclass of preferred heterocycles are heterocycleswhich function as an isostere of a cyclic but non-heterocyclicsubstitutent such as —CH₂—C(═O)-phenyl. Preferred examples of suchheterocycles include, but are not limited to, benzimidazolyl,benzofuranyl, 30 benzothiophenyl, benzoxazolyl, benzthiazolyl,benzisoxazolyl, furanyl, imidazolinyl, 1H-indazolyl, indolinyl,isoindolinyl, isoquinolinyl, oxazolyl, piperidinyl, pyrazinyl,pyridinyl, pyrimidinyl, quinolinyl, thiazolyl, thiophenyl, and1,2,3-triazolyl.

As used herein, the term “aryl”, or aromatic residue, is intended tomean an aromatic moiety containing the specified number of carbon atoms,such as phenyl, pyridinyl and naphthyl.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of Formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Synthesis

Throughout the details of the invention, the following abbreviations areused with the following meanings:

Reagents: MCPBA m-chloroperoxybenzoic acid DIBAL diisobutyl aluminumhydride Et₃N triethylamine TFA trifluoroacetic acid LAH lithium aluminumhydride NBS N-bromo succinimide Red-Al Sodiumbis(2-methoxyethoxy)aluminum hydride Pd₂dba₃Tris(dibenzylideneacetone)dipalladium(0) ACE-Cl2-chloroethylchloroformate Solvents: THF tetrahydrofuran MeOH methanolEtOH ethanol EtOAc ethyl acetate HOAc acetic acid DMF dimethyl formamideDMSO dimethyl sulfoxide DME dimethoxyethane Et₂O diethylether iPrOHisopropanol MEK methyl ethyl ketone Others: Ar aryl Ph phenyl Me methylEt ethyl NMR nuclear magnetic resonance MHz megahertz BOCtert-butoxycarbonyl CBZ benzyloxycarbonyl Bn benzyl Bu butyl Pr propylcat. catalytic mL milliliter nM nanometer ppm part per million mmolmillimole mg milligram g gram TLC thin layer chromatography HPLC highpressure liquid chromatography RPM revolutions per minute rt roomtemperature aq. aqueous sat. saturated

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

The preparation of compounds of Formula (I) of the present invention maybe carried out in a convergent or sequential synthetic manner. Detailedsynthetic preparations of the compounds of Formula (I) are shown in thefollowing reaction schemes. The skills required in preparation andpurification of the compounds of Formula (I) and the intermediatesleading to these compounds are known to those in the art. Purificationprocedures include, but are not limited to, normal or reverse phasechromatography, crystallization, and distillation.

Several methods for the preparation of the compounds of the presentinvention are illustrated in the schemes and examples shown below. Thesubstitutions are as described and defined above.

Compounds of Formula (I) of this invention may be prepared as shown inScheme 1. Thus, preparation of an aryl hydrazine (III) is accomplished,for example, by treatment of a corresponding substituted aniline (II)with NaNO₂ followed by reduction of the N-nitroso intermediate with areducing agent such as LAH or zinc and an organic acid, such as aceticacid or trifluoroacetic acid at low temperature. Assembly of the coretetracyclic intermediate indole (V) is accomplished by Fischer indolecyclization of the aryl hydrazine and a suitably substituted ketone(i.e. (IV)) by methods described by, but not limited to, R. J. Sundberg,“Indoles, Best Synthetic Methods” 1996, Academic Press, San Diego,Calif. For example, treatment of the aryl hydrazine (III) as the freebase or the corresponding mineral acid salt with the ketone (IV) (R¹═H,Bn, CBZ, CO₂Et, etc) in an alcoholic solvent in the presence of mineralacid affords the indoles (V) as the free bases (after treatment with aq.NaOH). Reduction of the indoles 0to the corresponding cis or transsubstituted dihydroindoles is accomplished by, for example, treatmentwith hydrogen in the presence of a catalyst such as platinum oxide orpalladium on carbon, or with a metal such as zinc and a mineral acidsuch as hydrochloric acid, or with sodium and liquid ammonia, or withborane-amine complex such as borane-triethylamine in tetrahydofuran, orpreferably by treatment with NaCNBH₃ in an acid such as acetic ortrifluoroacetic acid.

The corresponding enantiomers can be isolated by separation of theracemic mixture of (I) on a chiral stationary phase column utilizingnormal or reverse phase HPLC techniques, the details of which aredescribed in the examples. Alternatively, a diastereomeric mixture of(I) can be prepared by treatment of (I, R¹═H) with an appropriate chiralacid (or suitably activated derivative), for example dibenzoyl tartrateor the like (see, for example, Kinbara, K., et. al., J. Chem . Soc.,Perkin Trans. 2, 1996, 2615; and Tomori, H., et. al., Bull. Chem. Soc.Jpn., 1996, 3581). The diastereomers would then be separated bytraditional techniques (i.e. silica chromatography, crystallization,HPLC, etc) followed by removal of the chiral auxiliary to affordenantiomerically pure (I).

In the cases where the carboline nitrogen has been protected (VI) (i.e.R¹=Boc, Bn, CBZ, CO₂R), it may be removed under a variety of conditionsas described in Greene, T. W., Wuts, P. G. W., “Protective Groups inOrganic Synthesis, 2nd Edition”, John Wiley and Sons, Inc., New York,pages 309-405, 1991. The free secondary amine could then be alkylated,for example, by treatment with a suitably substituted alkyl halide(R¹Cl, or R¹I) and a base to afford additional compounds of type (I), asdescribed, for example, by Glennon, R. A., et. al., Med. Chem. Res.,1996, 197.

Alternatively, compounds of Formula (I) can be prepared as described inScheme 2. Treatment of an ortho halonitrobenzene compound (VII) with anucleophilic alkyl halide (X═OH, SH, NHR, (VIII)) (as described byKharasch, N., Langford, R. B., J. Org. Chem., 1963, 1903) and a suitablebase followed by subsequent reduction of the corresponding nitroarylderivative to the aniline (IX). The reduction may be accomplished with avariety of reducing agents, for example, LAH, SnCl₂, NaBH₄, N₂H₄, etc.or with hydrogen in the presence of a suitable catalyst, such aspalladium on carbon, or platinum oxide, etc., (see Hudlicky, M.,“Reductions in Organic Chemistry”, Ellis Horwood, Ltd., Chichester, UK,1984). Formation of the aryl hydrazine (X) may be accomplished asdescribed previously in Scheme 1 or more directly by treatment of theaniline (IX) with aq. hydrochloric acid, stannous chloride and NaNO₂ atroom temperature (see, Buck, J. S., Ide, W. S., Org. Syn., Coll. Vol.,2, 1943, 130). This primary aryl hydrazine (X) can then be cyclizedunder Fischer indole cyclization conditions as detailed above forcompound (V), to afford the indole (XI) as the corresponding salt. Upontreatment of the indole (XI) with a base such potassium hydroxide orpotassium t-butoxide in a solvent such as DME or THF affords thetetracyclic indole intermediates (V). These indoles can also be reducedto the corresponding cis or trans indolines (I) as described previouslyin Scheme 1.

Still another related route to compounds of Formula (I) is shown inScheme 3. Initiating the synthesis with a nitrobenzene derivative suchas (XII), this approach allows for a variety of derivatization. Morehighly substituted nitrobenzenes can be obtained by traditionalsynthetic manipulation (i.e. aromatic substitution) and are known bythose in the art (see Larock, R. C., Comprehensive OrganicTransformations, VCH Publishers, New York, 1989): Treatment ofnitrobenzene derivative with a reducing agent such as LAH, etc., asdescribed previously (see Hudlicky, et. al.), affords the correspondinganiline intermediate. Subsequent formation of the hydrazine followed byFischer indole cyclization with a suitably functionalized ketone asdescribed above (i.e. Scheme 1, (III) to (V)) affords the g-carbolineindole (XIII). At this point the fused ring may be appended bycondensation of a haloalkyl carboxylic acid or a related activatedcarboxylic acid (i.e. acid chloride, mixed anhydride, etc.) such as(XIV). Reduction of the resultant heterocyclic carbonyl may be effectedwith various reducing agents, for example, sodium borohydride,diisobutyl aluminum hydride and the like (see Larock, R. C.,Comprehensive Organic Transformations, VCH Publishers, New York, 1989and/or Hudlicky, M., “Reductions in Organic Chemistry”, Ellis Horwood,Ltd., Chichester, UK, 1984) to afford the tetracyclic indoles (V).Further reduction of the indole (V) to the indolines (I) is as describedpreviously in Scheme 1.

Preparation of the aniline precursors (II) to the Fischer indolecyclizations is shown in Scheme 4. Treatment of a suitablyortho-functionalized aniline (XVI) with a chloroalkyl carboxylic acid orester (or equivalent substrate, i.e. acrylic acid, acryloyl chloride,etc.) and concomitant condensation, followed by reduction of theresultant heterocyclic carbonyl with a reducing agent such as LAH,DIBAL, or Red-Al affords the fused heterocyclic benzene derivatives(II). More diverse intermediates of (II) may be obtained by formation ofthe ortho substitiuted aniline from the corresponding ortho substitutednitobenzenes and concomitant reduction of the nitro moiety as describedabove. Furthermore, aromatic substitution of the fluoro (or other haloderived nitrobenzene) functionality of (XV) for an oxygen, or sulphurmoiety is accomplished, for example, by treatment of (XV) with anucleophile, such as sodium sulfide or an alcohol, followed by formationof the requisite thiophenol or phenol, respectively, using standardtechniques known by those in the art (see Larock, R. C., ComprehensiveOrganic Transformations, VCH Publishers, New York, 1989, page 481).Reduction of the nitro as before affords the substituted anilines (XVI).

An alternate approach to the substituted fused anilines (II) is shown inScheme 5. Treatment of the phenol (X═OH), thiophenol (X═SH), or othernucleophilically aromatic substituted derivative (XVII) with, forexample, a haloalkyl carboxylic acid (or equivalent activatedhaloalkylcarboxylic acid, (i.e. acid halide, mixed anhydride, acrylicacid, acryloyl chloride, etc.), affords the derivative (XVIII) whichwhen treated under Friedel-Crafts acylation conditions (see Ed. G. A.Olah, “Friedel-Crafts and Related Reactions”, J. Wiley and Sons, NewYork, 1964, Vol 3, Pts 1 and 2 or Chem. Rev., 1955, 229, or Olah, G. A.,“Friedel-Crafts Chemistry”, Wiley Interscience, New York, 1973, forvarying conditions and protocols), i.e. strong Lewis acids (AlCl₃,FeCl₃, etc.), affords the cyclic alkylphenones (XIX). Incorporation ofthe nitrogen functionality can be accomplished in several ways. Forexample, Schmidt rearrangement (as described by Smith, P. A. S., J. Am.Chem. Soc., 1948, 320) is effected by treatment of the carbonylderivative (XIX) with NaN₃ and methanesulfonic acid to afford thebicyclic lactam (XX). Alternatively, this transformation may be carriedout under Hoffmann rearrangement protocol (see, for example, Dike, S.Y., et. al., Bioorg. Med. Chem. Lett., 1991, 383), by initial formationof the oxime derivative of (XXI) by treatment with hydroxylaminehydrochloride. Subsequent rearrangement to the lactam is efficientlyaccomplished by heating in polyphosphoric acid to afford the lactam(XX). Reduction of the lactam (XX) can be accomplished with a variety ofreducing agents, for example, DIBAL, Red-Al and the like to afford theaniline (II).

The preparation of compounds of Formula (I) with additional diversity offunctionalization of the aromatic A ring of the tetracycle is shown inScheme 6 and Scheme 7 and described here. Due to the nature of thesynthetic route of Scheme 1 to derivatives of Formula (I), compoundswith halogen substituents on the A-ring are difficult to prepare.However, bromination of the indolines (I, R⁸═H) when the amine isprotected, for example, with the Boc or CBZ protecting groups, with, forexample, NBS in DMF affords the R⁸ brominated derivatives (XXII). Theseactivated aryl derivatives (XXII) act as excellent counterparts for anumber of important synthetic transformations.

For example, biaryl coupling is accomplished under Suzuki couplingprotocol. For a review and leading references of palladium catalyzedcross coupling reactions, see Miyaura, N., Suzuki, A., Chem. Rev., 1995,2457. One such procedure entails treatment of the aryl bromide (XXII)with a functionalized aryl boronic acid (XXIII) in the presence of acatalytic Pd(0) species, such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, Pd(OAc)₂,Pd₂(dba)₃ and a suitable ligand such as PPh₃, AsPh₃, etc., or other suchPd(0) catalyst, and a base such as Na₂CO₃ or Et₃N in a suitable solventsuch as DMF, toluene, THF, DME or the like, to afford the indolines(XXIV). Alternatively formation of the indole boronic acid from thebromine derivative (XXII) (i.e. (I, R⁸═B(OH)₂)) would allow for greaterdiversity in the subsequent coupling of this indole boronic acid withcommercially available haloaromatic derivatives in a similar Suzukicoupling strategy as-described above to afford the indolines (XXIV).

Similarly biaryl coupling of the bromine derivatives (XXV), readilyobtained by the synthetic sequence exemplified in Scheme 2, (startingwith the suitably functionalized bromo nitrobenzenes (II)), is shown inScheme 7. This approach allows for the preparation of biaryl indoles aswell as the corresponding indoline derivatives. Protection of the aminefunctionality must be carried out if R¹═H (see Greene et.al forprotections of amines). This is readily accomplished, for example, bytreatment of bromo derivatives (XXV) with (Boc)₂O in aqueous sodiumhydroxide and dioxane. Subsequent Suzuki coupling with a variety of arylboronic acids is carried out as described above in Scheme 6, to affordthe biaryl adducts (XXVI). This protocol is amenable to R⁷, R⁸, and R⁹bromide, iodide, triflates, and/or diazo derivatives (see Miyaura, N.,Suzuki, A., Chem. Rev., 1995, 2457, for a review of aryl couplings).

Furthermore and as an extension of this approach to a rapid preparationof a large array of biaryl indole and indoline derivatives, thesebromide derivatives (XXV) can be bound to a solid support and the Suzukicouplings can be carried out on solid support (see XXVIII) asillustrated in Scheme 8. Towards that end treatment of indoline (XXV)with TFA in CH₂Cl₂, to remove the Boc protecting group, followedextraction from aqueous base provides the free amine (XXXVII). The freeamine can be loaded onto a suitable solid support such as (XXVIII) usingconditions well known to those skilled in the art. Thus,p-nitrophenylchloroformate Wang resin (XXVIII) which can be obtainedcommercially from sources such as Novabiochem, Inc. is swollen in asuitable solvent such as N-methyl pyrrolidinone and treated with 1.5equiv. of amine to afford the functionalized resin (XXIX). Suzukicouplings are then carried out in array format by treatment of resins(XXIX) with a suitable palladium source such as Pd(PPh₃)₄ or Pd(dppf)C1₂and a suitable base such as 2M aqueous K₂CO₃ or Na₂CO₃or triethylaminewith an excess (typically 5 equivalents) of an aryl boronic acid(procedures for solid-phase Suzuki and other palladium couplings arewell-known by those in the art, see for instance L. A. Thompson and J.A. .Ellman, Chem. Rev. 1996, 96, (1), 555-600). The coupling may berepeated to ensure complete conversion to the desired coupled product.Cleavage from the solid support by treatment with TFA affords thecorresponding indoles and indolines (XXX) as their TFA salts.

In addition, there exists a wide range of procedures and protocols forfunctionalizing haloaromatics, aryldiazonium and aryltriflate compounds.These procedures are well known by those in the art and described, forexample, by Stanforth, S. P., Tetrahedron, 1998, 263; Buchwald, S. L.,et. al., J. Am. Chem. Soc., 1998, 9722; Stille, J. K., et. al., J. Am.Chem. Soc., 1984, 7500. Among these procedures are biaryl couplings,alkylations, acylations, aminations, and amidations. The power ofpalladium catalyzed functionalization of aromatic cores has beenexplored in depth in the last decade. An excellent review of this fieldcan be found in J. Tsuji, “Palladium Reagents and Catalysts, Innovationsin Organic Synthesis”, J. Wiley and Sons, New York, 1995.

One such method to prepare compounds of Formula (I) with substituted R¹sidechains in a more direct manner is shown in Scheme 9. Alkylation ofthe indole or indoline derivatives (I, R¹═H) with a haloalkyl ester,such as ClCH₂(CH₂)_(p)CO₂Me, in the presence of NaI or KI and a basesuch as K₂CO₃, Na₂CO₃ or the like, in dioxane or THF or other suchsolvent while heating (see Glennon, R. A., et. al., Med. Chem. Res.,1996, 197) affords the R¹ alkylated esters. Subsequent formation of theactivated amides (XXXI) is accomplished by treatment of the ester withN,O-dimethylhydroxylamine hydrochloride and a Lewis acid such astrimethylaluminum or triethylaluminum in toluene (see, for example,Golec, J. M. C., et. al., Tetrahedron, 1994, 809) at 0° C. Treatment ofthe amide (XXXI) with a variety of organometallic agents, such asGrignard reagents R^(1a)MgBr, alkyl and aryl lithium reagents etc. (seeSibi, M. P., et. al., Tetrahedron Lett., 1992, 1941; and more generallyHouse, H. O., Modern Synthetic Reactions, W. A. Benjamin, Inc., MenloPark, Calif., 1972), in a suitable solvent such as THF, ether, etc. atlow temperatures affords the substituted ketones (XXXII).

Preparation of compounds of Formula (I) where m=0, k=1 is outlined inScheme 10 and described here. Fischer indole cyclization of thepreviously described hydrazine (III) with a known protected2,3-dioxopyrolidine (Carlson, E. H., et. al., J. Org. Chem., 1956, 1087)under a variety of typical cyclization conditions affords thetetracyclic indole (XXXIII). The reduction may be accomplished with avariety of reducing agents, for example, LAH, DIBAL, etc., to yield thepyrole fused indole (XXXIV). This derivative can then be deprotected andsubsequently alkylated as described previously (see Greene, T. W., Wuts,P. G. W., “Protective Groups in Organic Synthesis, 2nd Edition”, JohnWiley and Sons, Inc., New York, 1991, and Scheme 1), to give the R¹alkylated indole analogs (XXXV). Alternatively, reduction of the indoleto the indoline, as described previously (see Scheme 1), followed bydeprotection of the benzyl group to give (XXXVI) and alkylation givesaccess to the corresponding R¹ alkylated indoline derivatives (XXXVII).All the previously described methods to functionalize the aromatic ring,and to afford derivatives of varying R¹ sidecahins are applicable tothese cores.

EXAMPLES

Chemical abbreviations used in the Examples are defined above. Thedetailed processes for preparing the compounds of Formula (I) areillustrated by the following Examples. It is, however, understood thatthis invention is not limited to the specific details of these examples.The Examples as set forth below are intended to demonstrate the scope ofthe invention but are not intended to limit the scope of the invention.Proton nuclear magnetic resonance spectra (¹H NMR) were measured inchloroform-d (CDCl₃) unless otherwise specified and the peaks arereported in parts per million (ppm) downfield from tetramethylsilane(TMS). The coupling patterns are reported as follows: s, singlet; d,doublet; dd, doublet of doublets; t, triplet; q, quartet; m, multiplet;bs, broad singlet; bm, broad multiplet.

Example 4 ethyl1-fluoro-6,7,9,12-tetrahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(10H)-carboxylate

Step A:

p-Fluorothiophenol (5 g, 40 mmol) and β-propiolactone (2.8 g, 40 mmol)were dissolved in THF (36 mL of freshly distilled) and then placed in anice bath. 95% sodium hydride (1 g, 42.9 mmol) was added in smallportions over 1 hour. The reaction was allowed to stir at 0° C. for 2hours, then placed in the freezer overnight. The reaction was quenchedwith ice chips and then acidified with concentrated hydrogen chlorideuntil a pH of 2. The product was extracted with ethyl acetate (1×200 mL)and dichloromethane (2×200 mL), dried (sodium sulfate) and concentratedto give 3-[(4-fluorophenyl)sulfanyl]propanoic acid (7.08 g, 89%). ¹H NMR(CDCl₃, 300 MHz): δ 7.42-7.35 (m, 2H), 7.02 (t, 2H, J=8.6 Hz), 4.35 (t,1H, J=6.2 Hz), 3.10 (t, 2H, J=7.3 MHz), 2.63 (t, 2H, J=7.3 Hz) ppm.

Step B:

3-[(4-fluorophenyl)sulfonyl]propanoic acid (3 g, 15 mmol) was dissolvedin dichloromethane (30 mL ) and cooled to 0° C. in an ice bath. Oxalylchloride (10 mL) was added slowly, dimethyl formamide (1 drop) was addedand the reaction mixture was stirred at 0° C. for 0.5 hours. At whichpoint the reaction was concentrated under reduced pressure to a residue,then resuspended in dichloromethane and cooled to 0° C. in an ice bath,CS₂ (1 mL) was added and AlCl₃ (4 g, 15 mmol) was added slowly. Thereaction mixture was then allowed to warm to room temperature andstirred over night. Ice chips and water (250 mL) were added and stirred.Concentrated hydrogen chloride was added until pH of 2, and extractedwith dichloromethane (3×150 mL). Organics were combined, washed withbrine (1×100 mL) and water (1×100 mL), dried (sodium sulfate), andconcentrated to a yellow solid. The solid was purified by flash columnchromatography on 100 g silica gel, eluting 10% ethyl acetate in hexanesto give 6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (2.55 g, 93%). ¹HNMR (CDCl₃, 300 MHz): δ 7.80-7.76 (m, 1H), 7.27-7.23 (m, 2H), 7.15-7.09(m, 1H), 3.23 (t, 2H, J=6.4 Hz), 2.97 (t, 2H, J=6.4 Hz) ppm.

Step C:

6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (100 mg, 0.54 mmol ) wasdissolved in acetic acid (0.5 mL, 1.1 eq), sodium azide (71.2 mg, 1.1mmol) was added and mixture was heated to 50° C. Sulfuric acid (0.13 mL,4.3 eq) was added slowly and stirred at 50° C. for 1.5 hours. Ice chips(150 mg) were added and a green solid precipitated, this was filtered,washed with water and dried to give7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (80 mg, 24%). ¹H NMR(CDCl₃, 300 MHz): δ 7.77 (s-broad, 1H), 7.69 (t, 1H, J=7.3 Hz),6.94-6.82 (m, 2H), 3.42 (t, 2H, J=7 Hz), 2.63 (t, 2H, J=6.7 Hz) ppm.

Step D: #

7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (76 mg, 0.38 mmol)dissolved in toluene (1 mL) and cooled to 0° C. in an ice bath. Red-Al(275 mL, 0.91mmol) was added and then the reaction allowed to warm toroom temperature. The reaction was heated at reflux for 1.5 hours. 1 Nsodium hydoxide was added slowly until pH>10, this was stirred for 10minutes, extracted with dichloromethane (3×25 mL), washed with water,and dried (sodium sulfate). The concentrated organics were purified bypreparative thin layer chromatography on silica gel and eluted with 50%ethyl acetate in hexanes to give7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (30.8 mg, 93%). ¹H NMR(CDCl₃, 300 MHz): δ 7.32 (t, 1H, J=7.5 Hz), 6.53-6.42 (m, 2H), 4.09(s-broad, 1H), 3.31-3.27 (m, 2H), 2.83-2.79 (m, 2H), 2.11-2.04 (m, 2H)ppm.

Step E:

7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (423 mg, 2.3 mmol) wasdissolved in acetic acid (1.15 mL)at 0° C. in an ice bath. 2.7 M aqueoussodium nitrite (1 mL) was added and this was stirred over night. Waterwas added (100 mL) and extracted with dichloromethane (3×50 mL), theorganics were combined and concentrated to give7-fluoro-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (449 mg, 92%).¹H NMR (CDCl₃, 300 MHz): δ 7.43 (t, 1H, J=7.1 Hz), 7.30 (dd, 1H, J=9.1Hz, J=9.2 MHz), 7.26-7.00 (m, 1H), 4.18 (t, 2H, J=5.8 Hz), 2.86 (t, 2H,J=7.2 Hz), 2.17-2.04 (m, 2H) ppm.

Step F:

7-fluoro-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (449 mg, 2.11mmol) was suspended in THF (1 mL of freshly distilled) and cooled to 0°C. in an ice bath. Lithium aluminum hydride (80 mg, 2.11 mmol) was addedin a portion-wise fashion. The flask was removed from the ice bath andallowed to warm to room temperature and was stirred for 2 hours. Water(0.08 mL) was added and stirred for 10 minutes. 15% sodium hydroxide(0.08 mL) was added stirred for 10 minutes. Water (0.024 mL) was addedand stirred for 10 minutes. The reaction was extracted withdichloromethane (2×25 mL). The organics were concentrated to a residue,then taken up in minimal amount of dichloromethane and then hydrogenchloride in ether (1 M) was added until precipatation formed, theprecipatate was filtered off to give7-fluoro-3,4-dihydro-1,5-benzothiazepin-5(2H)-amine (471 mg, 95%). ¹HNMR (CD₃OD, 300 MHz): δ 7.59 (t, 1H, J=7.5 Hz), 7.28 (d, 1H, J=9.9 Hz),7.00 (t, 1H, J=8.2 Hz), 3.52 (t, 1H, J=7.5 Hz), 2.92-2.86 (m, 1H),2.72-2.70 (m, 2H), 2.40-2.31 (m, 1H), 2.2-2.18 (m, 2H) ppm.

Step G:

7-fluoro-3,4-dihydro-1,5-benzothiazepin-5(2H)-amine (470 mg, 2 mmol),1-carbethoxy-4-piperidone (0.3 mL, 2mmol), and ethanol (11 mL) were allcombined and heated to reflux overnight. The reaction was concentratedto a residue and purified by flash column chromatography on 20 g ofsilica, eluting with (1%, 2%, 3%, and 10%) methanol in dichloromethaneto give the title compound (115 mg, 54%). ¹H NMR (CDCl₃, 300 MHz): δ6.84 (t, 1H, J=6.4 Hz), 6.50 (t, 1H, J=6 Hz), 4.72 (s-broad, 2H), 4.47(t, 2H, J=5.8 Hz), 4.20-4.13 (m, 2H), 3.82 (s-broad, 2H), 3.27 (t, 2H,J=6.7 Hz), 2.69 (s-broad, 2H), 2.27 (q, 2H, J=6.1 Hz), 1.36 (t, 3H,J=6.9 Hz) ppm. Mass Spec (ESI): 335 (base M+H).

Example 1968-[4-(4-fluorophenyl)-4-oxobutyl]-7,8,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

7,8,9,10-hexahydro-2-oxo-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one(108 mg, 0.48 mmol) was dissolved in 1.2 mL of MEK. KI (80 mg, 0.48mmol) and K₂CO₃ (193 mg, 1.40 mmol), and 4-chloro-4′-fluorobutyrophenone(124 mg, 0.62 mmol) were added. The suspension was refluxed for 48 hrsand then cooled to rt. The suspension was filtered and the residue waswashed with CH₂Cl₂ (5mL). The solution was concentrated in vacuo. Theresidue was purified by column chromatography (10% MeOH—CH₂Cl₂) toafford the title compound (20.1 mg, 11%) as a white amorphous solid. ¹HNMR (CDCl₃, 300 MHz) δ 7.90-7.94 (m, 2 H), 7.00-7.05 (m, 3H), 6.84-6.89(m, 1H), 6.42 (d, 1H, 7.0 Hz), 4.74 (s, 2H), 3.66 (s, 2H), 3.00 (t, 2H,6.9 Hz), 2.78-2.90 (m, 2H), 2.50-2.77 (m, 4H), 1.90-2.05 (m, 2H) ppm. MS(ESI): 392.2 (base, M+H).

Example 1974-((8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indol-11(8aH)-yl)-1-(4-methylphenyl)-1-butanonehydrochloride

General Procedure A:

To a suspension of(8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole0.5 mmol) in 1,4-dioxane (3 mL) was added the correspondingchlorobutyrophenone (0.5-1.0 mmol), potassium iodine (100 mg) andpotassium carbonate (300 mg). The reaction mixture was heated at refluxfor 2 days. The solvent was removed under reduced pressure. The residuewas treated with water (50 mL) and extracted with diethyl ether ( 3×50mL). The ether extract was washed with brine (150 mL), dried over MgSO₄,filtered and concentrated to a residue. The residue was purified byflash column chromatography (Silica gel, CH₂Cl₂:CH₃OH 9:1). The productwas dissolved in ether (2 mL) and stirred at 0° C. for 10 minutes, added1N HCl in ether (0.5 mL) at 0° C. The white crystalline solid wascollected by filtration to give the title compound in 50-90 % yield.

General procedure B:

To a suspension of(8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-ptrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole0.5 mmol) in 1,4-dioxane (3 mL) was added the corresponding alkyl halide(0.5-1.0 mmol), potassium iodine (100 mg) and triethylamine (1.5 mmol).The reaction mixture was heated at reflux for 2 days. The solvent wasremoved under reduced pressure. The residue was treated with water (50mL) and extracted with diethyl ether ( 3×50 mL). The ether extract waswashed with brine (150 mL), dried over MgSO₄, filtered and concentratedto a residue. The residue was purified by flash column chromatography(Silica gel, CH₂Cl₂:CH₃OH 9:1). The product was dissolved in ether (2mL) and stirred at 0° C. for 10 minutes, added 1N HCl in ether (0.5 mL)at 0° C. The white crystalline solid was collected by filtration to givethe title compound in 50-90 % yield.

The title compound was prepared from addition of4-chloro-4′-methylbutyrophenone to(8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-ptrido[4,3-b][1,4]thiazepino[2,3,4-hi]indolefollowing General procedure A above. ¹H NMR (300 MHz, CDCl₃) δ 7.86 (d,J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 6.94 (d, J=7.7 Hz, 1H), 6.84 (d,J=7.3 Hz, 1H), 6.61 (dd, J=7.7 Hz, 7.3 Hz, 1H), 3.72-3.86 (m, 2H),3.44-3.59 (m, 2H), 3.22-3.27 (m, 1H), 2.98-3.14 (m, 7H), 2.41 (s, 3H),2.68-2.84 (m, 2H), 1.89-2.16 (m, 6H) ppm. MS-ESI: 407 [MH]⁺

Example 203(8aS,12aR)-11-[3-(4-fluorophenoxy)propyl]-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indolehydrochloride

The title compound was prepared from addition of3-chloro-1-(4-fluorophenoxy)propane to(8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-ptrido[4,3-b][1,4]thiazepino[2,3,4-hi]indolefollowing General procedure A of Example 197. ¹H NMR (300 MHz, CDCl₃) δ6.91-7.00 (m, 3H), 6.79-6.87 (m, 3H), 6.62 (dd, J=7.7 Hz, 7.3 Hz, 1H),3.97 (t, J=6.2, 2H), 3.70-3.87 (m, 1H), 3.50-3.60 (m, 1H), 3.18-3.31 (m,2H), 2.90-3.12 (m, 2H), 2.70-2.80 (m, 2H), 2.40-2.62 (m, 2H), 2.22-2.38(m, 1H), 1.90-2.11 (m, 7H) ppm. MS-ESI: 399 [MH]⁺

Example 2104-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-pyridinyl)-1-butanonehydrochloride

The title compound was prepared from addition of the of4-chloro-1-(4-pyridyl)butan-1-one to3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinefollowing General procedure A of Example 197. ¹H NMR (300 MHz, CDCl₃) δ8.79 (dd, J=4.4 Hz, 1.8 Hz, 2H), 7.74 (dd, J=4.4 Hz, 1.4 Hz, 2H), 6.64(dd, J=7.4 Hz, 7.6 Hz, 1H),6.49 (d, J=6.9 Hz, 1H), 6.39 (d, J=7.7 Hz,1H), 3.54-3.62 (m, 1H), 3.23-3.31 (m, 2H), 3.13-3.17 (m, 1H), 2.95-3.03(m, 2H), 2.85 (s, 3H), 2.76-2.84 (m, 2H), 2.57-2.60 (m, 1H), 2.31-2.41(m, 1H), 2.22 (td, J=11.7 Hz, 2.9 Hz, 1H), 1.92-2.02 (m, 3H),1.83-1.88(m, 1H), 1.66-1.76 (m, 2H) ppm. MS (CI, NH₃) m/e 376 (base, M+H⁺).

The title compound was separated into the corresponding enantiomers bychiral chromatographic separation. (Chiralpak AD column,methanol/ethanol 50/50): ¹H NMR (300 MHz, CDCl₃) δ 8.79 (dd, J=4.4 Hz,1.8 Hz, 2H), 7.74 (dd, J=4.4 Hz, 1.4 Hz, 2H), 6.64 (dd, J=7.4 Hz, 7.6Hz, 1H),6.49 (d, J=6.9 Hz, 1H), 6.39 (d, J=7.7 Hz, 1H), 3.54-3.62 (m,1H), 3.23-3.31 (m, 2H), 3.13-3.17 (m, 1H), 2.95-3.03 (m, 2H), 2.85 (s,3H), 2.76-2.84 (m, 2H), 2.57-2.60 (m, 1H), 2.31-2.41 (m, 1H), 2.22 (td,J=11.7 Hz, 2.9 Hz, 1H), 1.92-2.02 (m, 3H),1.83-1.88 (m, 1H), 1.66-1.76(m, 2H) ppm. MS (CI, NH₃) m/e 376 (base, M+H⁺).

Example 211(6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Step A:

The procedure described in Example 4, Steps E through G, was utilized toprepareethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylatefrom the corresponding amine, 1,3,4-trihydroquinoxalin-2-one, and ethyl4-oxopiperidinecarboxylate. This indole (5.74 g, 19.2 mmol) wasdissolved in TFA (100 mL). The reaction was cooled to 0° C. NaCNBH₃(3.96 g, 63.0 mmol) was added in small portions over 30 min, keeping thetemperature less than 5° C. The reaction was stirred at r.t. for 4 hr.Ice was added to the reaction flask, and the reaction was basified with50% NaOH until pH=12. Water (80 mL) was added to dissolve theprecipitate. The reaction was extracted with CHCl₃ (3×200 mL). Thecombined organic layers were washed with brine, dried, and concentratedto afford ethyl(6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(4.41 g, 77%). ¹H NMR (CDCl₃, 300 MHz) δ 8.45 bs, 1H), 6.86 (d, J=7.4Hz, 1H), 6.74 (dd, J=7.7 Hz, 7.7 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 4.15(q, J=7.0 Hz, 2H), 3.89-3.993 (m, 2H), 3.41-3.47 (m, 2H), 3.33-3.41 (m,2H), 3.12-3.31 (m, 1H), 2.69-2.75 (m, 2H), 1.90-1.92 (m, 2H), 1.28 (t,J=7.3 Hz, 3H) ppm. MS-APcI: 302 [MH]⁺

Step B:

Toethyl-(6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(4.41 g, 14.6 mmol) was added 1M BH₃ THF complex solution (36.6 mL). Thereaction was heated under reflux for 5 hr. After the reaction cooleddown to r.t, 6N HCl ( 40 mL) was added dropwise with chilling. Thereaction solution was heated under reflux for 30 minutes. After cooleddown to r.t., 1N NaOH was added to adjust the pH to 8. The reaction wasextracted with CH₂Cl₂ (2×200 mL). The combined organic layers werewashed with brine, dried over MgSO₄, and concentrated to afford ethyl(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(4.10 g, 98%). The product was used in next step without furtherpurification. MS-APcI: 288 [MH]⁺

Step C:

To ethyl(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(4.10 g, 14.3 mmol) was added n-butanol (18.0 mL) and KOH powder (3.0g). The reaction was heated at 119° C. in a sealed tube for 18 hr. Thesolvent was removed under reduced pressure. To the residue was addedwater (30 mL) extracted with CH₂Cl₂ (3×50 mL). The combined organiclayers were washed with brine, dried over MgSO₄, and concentrated toafford the title compound as a pale yellow oil (2.70 g, 78%). MS-ESI:216 [MH]⁺

Example 2124-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

Step A:

To2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline(2.70 g, 10.8 mmol) was added 1N NaOH (40.0 mL) and dioxane (40.0 mL).Boc₂O was added in small portions in 30 minute at 0° C. The reaction wasstirred at r.t. for 18 hr. The reaction was extracted with CH₂Cl₂ (3×150mL). The combined organic layers were washed with brine, dried overMgSO₄, and concentrated to afford a residue which was purified by flashcolumn chromatography (Hexane/Ethyl acetate: 50/50) to affordtert-butyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.The racemate could be separated by Chiralcel OD column (5 cm×50 cm, 20u; IPA/Hexane: 8%) to afford the corresponding enantiomers.

Step B:

To either of the enantiomers oftert-butyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(790 mg, 2.25 mmol) were added 20% TFA/CH₂Cl₂ (5 mL), stirred at r.t.overnight. The solution was concentrated to a residue to afford the TFAsalt in 99% yield. To this indoline TFA salt (493.5 mg, 1.5 mmol) wasadded triethylamine (0.4 mL), K₂CO₃ (300 mg) KI (100 mg) and 1,4-dioxane( 6 mL). 4-Chloro-4′-fluorobutyrophenone (3.37 mmol) was then added andthe mixture was heated at 103° C. in a sealed tube for 2.4 hr. Thesolvent was removed under reduced pressure. To the residue was addedwater (30 mL) extracted with CH₂Cl₂ (3×50 mL). The combined organiclayers were washed with brine, dried over MgSO₄, and concentrated to aresidue. The residue was purified by flash column chromatography toafford the title compound (280 mg, 53% yield). ¹H NMR (CDCl₃, 300 MHz) δ7.97-8.02 ( m, 2H), 7.09-7.15 (m, 2H), 6.51-6.61 (m, 2H), 6.38 (dd,J=7.3 Hz, J=1.4 Hz, 1H), 3.64-3.72 (m, 2H), 3.26-3.49 (m, 2H), 3.13-3.24(m, 2H), 2.99-3.04 (m, 2H), 2.91-2.97 (m, 1H), 2.61-2.79 (m, 2H),2.43-2.53 (m, 2H), 2.34-2.43 (m, 1H), 1.95-2.13 (m, 4H) ppm. MS-ESI: 380[MH]⁺

Example 217(6bR,10aS)-8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride

Step A:

To a cold boron trifluoride etherate (280 mmol) solution was added3-fluorophenol or phenol (89 mmol) and 4-chlorobutyryl chloride (178mmol). The resulting solution was stirred at 130° C. for 18 hours. Thereaction mixture was cooled and poured into ice water (100 mL). Afterstirring for 10 minutes, the water mixture was extracted with ether(3×100 mL). The ether layer was washed with brine (100 mL), dried overMgSO₄, filtered and concentrated to a residue to afford4-chloro-1-(4-fluoro-2-hydroxyphenyl)butan-1-one and4-chloro-1-(2-hydroxyphenyl)butan-1-one in 52%-67% yield, which was usedin the following step without further purification.

Step B:

To pyridine (25 mL) was added the corresponding ketone from Step A (46.5mmol) and hydroxylamine hydrochloride (53.5 mmol). The resultant mixturewas stirred at ambient temperature overnight and then poured into diluteHCl (100 mL). The mixture was stirred for 5 minutes and extracted withether (3×50 mL). The ether layer was dried over MgSO₄, filtered andconcentrated to a residue to afford(1E)-4-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-butanone oxime and(1E)-4-chloro-1-(2-hydroxyphenyl)-1-butanone oxime in 99% yield, whichwere used in the following step without further purification.

Step C:

To acetic anhydride (10 mL ) was added the corresponding oxime from StepB (40.0 mmol). The reaction mixture was heated at 60° C. for 2 hours,then poured into ether (10 mL). The mixture was washed with sat. NaHCO₃solution (4×10 mL), then with brine (10 mL). The organic layer wasseparated, dried over MgSO₄, filtered and concentrated to afford2-[(1E)-N-(acetyloxy)-4-chlorobutanimidoyl]-5-fluorophenyl acetate and2-[(1E)-N-(acetyloxy)-4-chlorobutanimidoyl]phenyl acetate in 61%-75%yield.

Step D:

To the corresponding bis-acylated derivatives from Step C ( 5.2 mmol) inethanol (4 mL) was added KOH (14.4 mmol). The reaction mixture wasrefluxed for 2 hours, cooled down to rt, added ethyl acetate (10 mL),washed with brine (10 mL), dried over MgSO₄, filtered and concentratedto a residue. The residue was purified by silica gel flash columnchromatography (Ethyl acetate/Hexane: 3:7) to afford3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole and3-(3-chloropropyl)-1,2-benzisoxazole in 32% yield.

Step E:

The title compound was prepared from addition of3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole from Step D and(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinefollowing General procedure A, Example 197. ¹H NMR (300 MHz, CDCl3) δ7.63 (dd, J=8.8 Hz, 4.7 Hz, 1H), 7.20-7.24 (m, 1H), 7.03-7.10 (m, 1H),6.65 (dd, J=7.7 Hz, 7.7 Hz, 1H), 6.50 (d, J=7.3 Hz, 1H), 6.41 (d, J=7.3Hz), 3.73-3.77 (m, 1H), 3.55-3.62 (m, 1H), 3.21-3.32 (m, 3H), 2.91-3.10(m, 3H), 2.86 (s, 3H), 2.75-2.82 (m, 2H), 2.54-2.63 (m, 1H), 2.41-2.48(m, 1H), 1.95-2.11 (m, 6H) ppm. MS (CI, NH₃) m/e 407 (base, M+H⁺).

Example 218(6bR,10aS)-8-[3-(1,2-benzisoxazol-3-yl)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride

The title compound was prepared from addition3-(3-chloropropyl)-1,2-benzisoxazole from Step D Example 22 and(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinefollowing the General procedure A of Example 197. ¹H NMR (300 MHz,CDCl₃) δ 7.59-7.62 (m, 1H), 7.46-7.50 (m, 2H), 7.20-7.25 (m, 1H), 6.57(dd, J=7.7 Hz, 7.3 Hz, 1H), 6.43 (d, J=6.9 Hz, 1H), 6.33 (d, J=7.3 Hz),3.48-3.52 (m, 1H), 3.06-3.25 (m, 4H), 2.94-2.99 (m, 2H), 2.70-2.89 (m,4H), 2.79 (s, 3H), 2.20-2.65 (m, 3H), 1.92-2.07 (m, 4H) ppm. MS (CI,NH₃) m/e 389 (base, M+H⁺).

Example 255(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

The procedure described in Example 4, Steps E through G, was utilized toprepare ethyl2,3,9,10-tetrahydro-2-oxo-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylatefrom the corresponding amine, 1,3,4-trihydroquinoxalin-2-one, and ethyl4-oxopiperidinecarboxylate

Step A:

Sodium cyanoborohydride (4.0 g, 65 mmol) was added, in small portions,to a vigorously stirred solution of ethyl2,3,9,10-tetrahydro-2-oxo-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(11.97 g, 40 mmol) in trifluoroacetic acid (125 mL) cooled in anice-water bath, under nitrogen. After the addition was complete, themixture was stirred for 30 min and then poured slowly into ammoniumhydroxide (300 mL) containing ice followed by the addition of enough 1Nsodium hydroxide to make the mixture basic. The mixture was extractedwith dichloromethane (2×) and the extract was washed with water, driedover magesium sulfate, and evaporated to dryness to yield 10.89 g (90%)of ethyl(6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylateas an off-white powder, m.p. 167-168° C. (dec., sinters at 70° C.). ¹HNMR (CDCl₃, 300 MHz) δ 1.28 (t, J=7 Hz, 3H), 1.81-1.95 (m, 2H),3.13-3.22 (m,1H), 3.23-3.39 (m, 1H), 3.44 (d, J=14.7 Hz, 1H),3.41-3.51(m, 1H), 3.80-3.95 (m, 1H), 3.98 (d, J=14.7 Hz, 2H), 4.16 (q,2H), 6.59 (d, J=7.7 Hz, 1H), 6.74 (t, J=7.7 Hz, 1H), 6.83 (d, J=7.7 Hz,1H), 8.17 (s, 1H) ppm. MS (CI): 302 (M+H⁺).

Step B:

Sodium hydride (900 mg of 60% dispersion in oil; 22.5 mmol) was washedwith hexane, and suspended in anhydrous dimethylformamide (5 mL). Thesuspension was added to a stirred solution of ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(6.02 g, 20 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen.After gas evolution had subsided, the mixture was cooled in ice-waterbath and treated with iodomethane (3.55 g., 25 mmol). The mixture wasstirred at room temperature for 1 h and then concentrated. The residuewas treated with water and extracted with dichloromethane (2×) and theextract was washed with brine, dried over magnesium sulfate andevaporated to dryness to yield 5.48 g (87%) of ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylateas a tan solid, m.p. 149-151° C. (dec.). [M+H] calc. 316; found 316. ¹HNMR (CDCl₃, 300MHz) δ 1.28 (t, J=7.3 Hz, 3H), 1.85 to 1.93 (m,1H), 2.65to 2.82 (m, 1H),3.08 to 3.25 (m, 1H), 3.25 to 3.40 (m, 1H),3.30-3.50 (m,1H), 3.34 (s, 3H), 3.42 (d, J=14.3 Hz, 1H), 3.85 to 4.0 (m,1H), 4.02 (d,J=14.3 Hz, 1H, 4.15 (q, J=7.2 Hz, 4H), 6.76 (d, J=8.1 Hz, 1H), 6.83 (t,J=7.3 Hz, 1H), 6.90 (d, J=7.3 Hz, 1H). MS (CI): 316 (M+H⁺).

Step C:

A solution of borane in tetrahydrofuran (1M, 33 mL, 33 mmol) was addeddropwise to a stirred solution of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(5.24 g, 16.6 mmol) in anhydrous tetrahydrofuran (25 mL) under nitrogen.After the addition was complete, the mixture was stirred and heated atreflux for 1 h, cooled and treated with 6N hydrochloric acid (15 mL). Itwas then heated under reflux for 30 min, cooled and evaporated todryness under reduced pressure. The residue was dissolved in a minimumquantity of water and the solution basified with 1N sodium hydroxide andextracted with dichloromethane (2×). The extract was washed with water,dried over magnesium sulfate, and concentrated to yield 4.65 g (93%) ofethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylateas a viscous liquid. ¹H NMR (CDCl₃, 300 MHz) δ 1.28 (t, J=7 Hz, 3H),1.68-1.78 (m, 1H), 1.78-1.93 (m, 2H), 2.81-2.90 (m, 2H), 2.86 (s, 3H),3.05-3.26 (m, 2H), 3.26-3.38 (m, 2H), 3.56-3.75 (m, 2H), 3.79-3.87 (m,1H), 4.16 (q, J=7 Hz, 2H), 6.41 (d, J=8.1 Hz, 1H), 6.61 (d, J=8.1 Hz,1H), 6.67 (t, J=8.1 Hz, 1H) ppm. MS (CI): 302 (M+H⁺).

Step D:

Powdered potassium hydroxide (10.0 g) was added to a stirred solution ofethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(4.52 g, 15.0 mmol) in warm 1-butanol (50 mL) and the resulting mixturewas heated under reflux for 5 h. It was then evaporated under reducedpressure and the residue treated with water and extracted withdichloromethane (2×). The extract was washed with water, dried overmagnesium sulfate and concentrated to yield 3.27 g (95%) of the titlecompound as a viscous liquid. ¹H NMR (CDCl₃, 300 MHz) δ 1.74-1.93 (m,4H), 2.57-2.71 (m, 1H), 2.80-2.95 (m, 3H), 2.87 (s, 3H), 2.95-3.12 (m,2H), 3.26-3.38 (m, 3H), 3.55-3.64 (m, 1H), 6.41 (d, J=7.3 Hz, 1H), 6.51(d, J=7.3 Hz, 1H), 6.65 (t, J=7.3 Hz, 1H) ppm. MS (CI): 230 (M+H⁺)

Example 256(6bR,10aS)-3-ethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Utilizing the material from Example 255 Step A, the title compound wasprepared in analogous fashion using ethyl iodide as the alkyl halide andfollowing the procedure of Step B-D of Example 255, as a light brownamorphous solid. ¹H NMR (CDCl₃, 300 MHz) δ 1.15 (t, 3H), 1.70-2.01 (m,3H), 2.65-2.70 (t, J=9.6 Hz, 3H), 2.70-2.95 (m,2H), 2,95-3.13 (m, 2H),3.13-3.72 (m, 5H), 3.60-3.95 (m, 1H), 6.39 (d, J=8.0 Hz, 1H), 6.47 (d,J=7,4 Hz, 1H), 6,64 (t, J=7.3 Hz), 1H) ppm. MS (CI): 244 (M+H⁺).

Step B:

Ethyl(6bR,10aS)-3-ethyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 70%. MS (CI) 330 (M+H⁺).

Step C:

Ethyl(6bR,10aS)-3-ethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 70%. MS (CI): 316 (M+H⁺).

Example 257(6bR,10aS)-3-propyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Step A:

Utilizing the material from Example 255 Step A, the title compound wasprepared in analogous fashion using propyl iodide as the alkyl halideand following the procedure of Step B-D of Example 255, as an amorphoustan solid. ¹H NMR (CDCl₃, 300 MHz) δ 0.94 (t, 2H), 1.40-2.01 (m, 6H),2.65-2.70 (t, J=9.6 Hz, 2H), 2.70-2.95 (m, 2H), 2.95-3.45 (m, 7H)),3.3.60-3.95 (m, 1H), 6.37(d, J=7.7 Hz, 1H), 6.46 (d, J=7.0 Hz, 1H), 6.64(t, J=7.6 Hz) ppm. MS (CI): 258 (M+H⁺).

Step B:

Ethyl(6bR,10aS)-3-propyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 72%. MS (CI) 344 (M+H⁺).

Step C:

Ethyl(6bR,10aS)-3-propyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Light brown viscous liquid. Yield 69%. MS (CI): 330 (M+H⁺).

Example 258(6bR,10aS)-3-isopropyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Step A:

Utilizing the material from Example 255 Step A, the title compound wasprepared in analogous fashion using isopropyl iodide as the alkyl halideand following the procedure of Step B-D of Example 255, as a viscousbrown liquid. ¹H NMR (CDCl₃, 300 MHz) δ 1.18 (d, 6H), 1.60-1.67 (m, 1H),1.71-1.94 (m, 2H), 2.63-2.75 (m, 2H), 2.81-2.95 (m, 2H), 2.99-3.20 (m,2H), 3.30-3.55 (m, 3H), 3.99-4.12 (m, 1H), 6.45 (d, J=7.4 Hz, 2H), 6.65(t, J=7.3 Hz, 1H) ppm. MS (CI): 258 (M+H⁺).

Step B:

Ethyl(6bR,10aS)-3-isopropyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 69%. MS (CI) 344 (M+H⁺).

Step C:

Ethyl(6bR,10aS)-3-isopropyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 97%. MS (CI): 330 (M+H⁺).

Example 259(6bR,10aS)-3-butyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Step A:

Utilizing the material from Example 255 Step A, the title compound wasprepared in analogous fashion using n-butyl iodide as the alkyl halideand following the procedure of Step B-D of Example 255, as a viscousbrown liquid. ¹H NMR (CDCl₃, 300 Mhz) δ 0.95 (t, 3H), 1.30-1.45 (m, 2H),1.50-1.65 (m, 2H), 1.95-2.15 (m, 2H), 2.65-2.80 (m, 2H), 2.65-2.80 (m,2H), 2.85-3.08 (m, 1H), 3.08-3.22 (m, 3H), 3.22-3.40 (m, 6H), 3.68-3.78(m, 1H), 6.38 (d, J=7.1 Hz), 6.46 (d, J=7.1 Hz, 1H), 6.66 (t, J=7.7 Hz,1H) ppm. MS (CI): 436 (M+H⁺).

Step B:

Ethyl(6bR,10aS)-3-butyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 82%. MS(CI): 358 (M+H⁺).

Step C:

Ethyl(6bR,10aS)-3-butyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 92%. MS (CI): 344 (M+H⁺).

Example 260(6bR,10aS)-3-benzyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Step A:

Utilizing the material from Example 255 Step A, the title compound wasprepared in analogous fashion using benzyl iodide as the alkyl halideand following the procedure of Step B-D of Example 255, as a viscousliquid. ¹H NMR(CDCl₃, 300 MHz) δ 1.60-2.0 (m, 2H), 2.55-2.95(m, 4H),2.95-3.15 (m, 2H), 3.20-3.45 (m, 3H), 4,40 (q, J=16.1 Hz, 2H), 6.41 (d,J=7.1 Hz, 1H), 6.51 (d, J=7.1 Hz, 1H), 6.62 (t, J=7.1 Hz, 1H), 7.20-7.40(m, 5H) ppm. MS (CI): 306 (M+H⁺).

Step B:

Ethyl(6bR,10aS)-3-benzyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 80%. MS (CI) 392 (M+H⁺).

Step C:

Ethyl(6bR,10aS)-3-benzyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]quinoxaline-8(7H)-carboxylate.Viscous brown liquid. Yield 85%. MS (CI): 378 (M+H⁺).

Example 2614-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

A mixture of3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline(3.20 g, 14 mmol), 4-chloro-4′-fluoro-butyrophenone (4.21 g, 21 mmol),triethylamine (3 mL), potassium iodide (3.48 g, 21 mmol), dioxane (25mL), and toluene (25 mL) was stirred and refluxed for 15 h under anatmosphere of nitrogen and then evaporated under reduced pressure toremove the volatiles. The residue was triturated with a small volume ofdichloromethane and decanted from the insoluble material. The processwas repeated two more times and the combined dichloromethane solutionswas added to 0.5N solution of hydrogen chloride in ether(200 mL). Thesalt that separated was filtered off, washed with ether, dissolvedimmediately in a minimum quantity of water and the solution extractedwith ether. The ether extract was discarded and aqueous layer basifiedwith 10% aqueous sodium hydroxide. The resulting mixture was extractedwith dichloromethane (2×) and the extract dried over magnesium sulfateand stripped of the solvent under reduced pressure to yield 4.15 g (75%)of a highly viscous brown liquid. ¹H NMR (CDCl₃, 300 MHz) δ 1.79-2.13(m, 6H), 2.21-2.32 (m, 1H), 2.32-2.44 (m, 2H), 2.60-2.71 (m, 1H),2.75-2.92 (m, 2H), 2.86 (s, 3H), 2.98 (t, J=7.3Hz, 2H), 3.04-3.16 (m,1H), 3.16-3.35 (m, 2H), 3.55-3.64 (m, 1H), 6.39 (d, J=8.1 Hz, 1H), 6.50(d, J=8.1 Hz, 1H), 6.64 (t, J=7.7 Hz, 1H), 7.12 (t, 2H), 8.01 (m, 2H)ppm. MS (CI): 394 (M+H⁺).

The above compound was resolved into its enantiomers on chiral HPLCcolumn.4-((6bS,10aR)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.Viscous tan liquid. [a]^(D)=−36.8° (c=0.886, CHCl₃). MS (CI): 394(M+H⁺).

4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.Viscous tan liquid. [a]^(D)=+33.6° (c=0.646, CHCl₃). MS (CI): 394(M+H⁺).

Example 2624-((6bR,10aS)-3-ethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

Treatment of(6bR,10aS)-3-ethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalineaccording to the procedure of Example 261 afforded the title compound ingood yield as a viscous brown liquid. ¹H NMR (300 MHz, CDCl₃) δ 1.15 (t,J=7.0 Hz, 3H), 1.75-2.03 (m, 5H), 2.20 to 2.30 (m, 1H), 2.30-2.42(m,2H), 2.63 to 2.77 (m, 3H), 2.77 to 2.87 (m,1H), 2.98 (t, J=7.0 HZ,2H), 3.04-3.43 (m, 5H), 3.64-3.72 (m, 1H0, 6.30 (d, J=7.7 Hz, 1H), (6.47d, J=7.7 Hz, 1H), 6.64 (d, J=7.7 Hz, 1H), 7.12 (t, J=8.5 Hz, 2H), 7.98to 8.03 (m, 2H) ppm. MS (CI): 408 (M+H⁺).

Example 2634-((6bR,10aS)-3-isopropyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

Treatment of(6bR,10aS)-3-isopropyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalineaccording to the procedure of Example 261 afforded the title compound ingood yield as a viscous, brown liquid. ¹H NMR (CDCl₃, 300 MHz) δ 1.18(d, J=6.6 Hz, 6H), 1.82-1.84 (m, 5H), 2.21-2.29 (m, 1H), 2.29-2.41 (m,2H), 2.64-2.68 (m, 2H), 2.79-2.87 (m, 1H), 2.98 (t, J=7.3 Hz, 2H),3.03-3.17 (m, 2H), 3.21-3.45 (m, 3H), 4.03 (dt, J=6.6, 2.3 Hz, 1H), 6.45(d, J=6.2 Hz, 2H), 6.64 (t, J=7.7 Hz, 1H), 7.12 (t, J=8.3 Hz, 2H),8.0-8.03 (m, 2H) ppm. MS(CI): 422 (M+H⁺).

Example 2644-((6bR,10aS)-3-benzyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

Treatment of(6bR,10aS)-3-benzyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalineaccording to the procedure of Example 261 afforded the title compound ingood yield as a viscous brown liquid. Yield 23%. ¹H NMR (CDCl₃, 300MHz,) δ 1.84-2.05 (m, 5H), 2.20-2.31 (m, 1H), 2.31-2.43 (m, 2H),2.64-2.72 (m ,1H), 2.72-2.80 (m, 1H), 2.80-2.89 (m, 1H), 2.99 (t, J=7.3Hz, 2H), 3.06-3.14 (m, 1H), 3.14-3.26 (m, 1H), 3.26-3.34 (m, 2H),3.65-3.74 (m, 1H), 4,43 (q, J=16.5 Hz, 2H), 6.40 (d, J=8.0 Hz, 1H), 6.50(d, J=7.0 Hz, 1H), ) 6.61 (t, J=8.1 Hz, 1H), 7.13 (t, J=8.5 Hz, 2H)7.20-7.35 (m, 5H), 8.00-8.03 (m, 2H) ppm. MS (CI): 470 (M+H⁺).

Example 269(6bR,10aS)-8-[3-(4-fluorophenoxy)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Treatment of(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalineaccording to the procedure of Example 203 afforded the title compound ingood yield as a viscous liquid. Yield 30%. ¹H NMR (CDCl₃, 300 MHz): δ1.85-2.10 (m, 5H), 2.20-2.40 (m, 1H)2.40-2.60 (m, 2H), 2.66-2.78 (m,1H), 2.78-2.95 (m, 2H), 2.87 (t, 3H), 3.10-3.35 (m, 4H), 3.55-3.70 (m,1H), 3.97 (t, J 6.2 Hz, 2H), 6.40 (d, J=7.7 Hz, 1H), 6.52 (d, J=7.3 Hz,1H), 6.65 (t, J=7.7 Hz, 1H), 6.79-6.90 (m, 2H), 6.96 (t, J=8.5 Hz, 2H)ppm. MS (CI): 382 (M+H⁺).

Example 274(6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

To a solution of tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(100 mg, 0.21 mmol) in THF (5.0 mL), BH₃-THF (1M in THF) (0.82 mL, 0.82mmol) was added dropwise. After addition was completed, the resultingreaction mixture was refluxed for 4 h, cooled to room temperature, andquenched cautiously with water (1.0 mL). The mixture was evaporated todryness under reduced pressure and the residue obtained was treated witho-xylene (10 mL) and 1-octene (5 mL) and heated at reflux for 4 h. Thereaction mixture was cooled to room temperature and concentrated todryness under reduced pressure to give tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylateas a white solid (50 mg, 58%).

The hydrochloride salt of the title compound was prepared fromtert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(50 mg) using the deprotection procedures described in Example 275, StepB. The salt formed was free-based with 6 N NaOH to give the titlecompound (31 mg, 80%). ¹H NMR (CD₃OD, 300 MHz) δ 1.80-1.90 (m, 1H),1.96-2.10 (m, 1H), 2.50 (m, 2H), 2.76-2.90 (m, 5H), 2.93-3.1 (m, 2H),3.20-3.50 (m, 4H), 3.50-3.60 (m, 2H), 6.40 (d, 1H), 6.5 (d, 1H),7.22-7.32 (m, 2H), 7.44 (d, 1H) ppm. MS-CI m/z=374 [C₂₀H₂₁Cl₂N₃+H]⁺

Example 275(6bR,10aS)-5-(2,4-dichlorophenyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride

Step A:

Typical Procedure for Suzuki Coupling: The corresponding bromo-indoline(1.0 equiv), the boronic acid (1.5-2 equivs) and barium hydroxide (1.5equivs) were stirred into a solution of water and DME, then heated at60° C. while bubbling through a stream of Argon gas for 20 min.

The reaction mixture was then cooled to room temperature andPd(PPh₃)₂Cl₂ (2.5-5 mol %) and PPh₃ (3 equivs based on Pd source) werequickly added and refluxing resumed for 4 hours. When the reaction wascompleted as shown by TLC, ethyl acetate was added and the mixture wasfiltered through a Celite bed. Organic layer was separated, dried oversodium sulfate and concentrated under reduced pressure to a yellow oil.This residue was purified on a flash column eluting with 10%EtOAc/Hexanes to give the desired product.

Tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(37 mg, 60%) was prepared via coupling of tert-butyl (6bR,10aS)-5-bromo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(50 mg, 0.13 mmol) with 2,4-dichlorophenyl boronic acid (74 mg, 0.39mmol) as illustrated above using the general procedure for Suzukicoupling. ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H), 1.82-1.96 (m, 2H),2.74-2.82 (m, 1H), 2.99-3.05 (m, 1H), 3.16-3.22 (m, 2H), 3.33-3.39 (m,1H), 3.43-3.50 (m, 1H), 3.52-3.57 (m, 1H), 3.62-3.69 (m, 1H), 3.43-3.50(m, 1H), 3.52-3.57 (m, 1H), 3.62-3.69 (m, 1H), 3.71-3.79 (m, 1H),3.80-3.85 (m, 1H), 3.89-4.14 (m, 1H), 6.44 (s, 1H), 6.59 (s, 1H), 7.22(s, 2H), 7.42 (s, 1H) ppm.

Step B:

General procedure for removal of Boc protecting group: The indoline(100-150 mg) is mixed with cold ethanolic hydrochloric acid (4M) (5 mL),and the solution is stirred for 10 min at 0° C. The solvent is removedunder reduced pressure and the residue is disolved in hot acetonitrilewith a small amount of methanol. Upon cooling to room temperature, thedesired salt is obtained as a crystalline material.

(6bR,10aS)-5-(2,4-dichlorophenyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,41:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride (57 mg, 78%) was formed from tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(110 mg) using the deprotection procedure described above to afford thetitle compound. ¹H NMR (CD₃OD, 300 MHz) δ 1.80-1.92 (m, 1H), 1.96-2.10(m, 1H), 2.5-2.69 (m, 2H), 2.76-2.90 (m, 2H), 2.97-3.1 (m, 2H),3.35-3.50 (m, 4H), 3.57-3.70 (m, 2H), 6.40 (d, 1H), 6.5 (d, 1H),7.22-7.32 (m, 2H), 7.44 (d, 1H) ppm. MS-CI m/z=361 [C₁₉H₁₉Cl₂N₃+H]⁺

Example 2764-((6bR,10aS)-5-bromo-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

Typical procedure for alkylation of carbolines: A mixture of indolinehydrochloride (188 mg, 0.7 mmol) in dioxane (4 mL) was treated withHunig's base (10 equivs) and heated to reflux for 15 min. To the cooledreaction mixture was added 4-chloro-4′-fluoro-butyrophenone (5 equivs),KI (0.9 equivs), then the whole mixture was refluxed for 48 h. Thereaction was then diluted with chloroform (20 mL) and extracted oncewith saturated solution of ammonium chloride (10 mL) and twice withice-cold water (100 mL). The organic layer was dried over sodium sulfateand concentrated to dryness under reduced pressure. The residue waspurified by flash chromatography eluting with a gradient ofhexane/ethylacetate (e.g. 96:4 to 50:50), following with a gradientmethanol/dichloromethane (e.g. 1:99 to 3:97) to give the desiredproduct.

The title compound (271 mg, 95%) was obtained from the alkylation of the(6bR,10aS)-5-bromo-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride (200 mg, 0.65 mmol) with 4-chloro-4′-fluorobutyrophenone(0.53 mL, 3.24 mmol) using the general procedure described above. ¹H NMR(CDCl₃, 300 MHz) δ 2.00-1.30 (m, 4H), 1.82-2.40 (m, 4H), 2.66-2.80 (m,2H), 2.86 (s, 3H), 3.07-3.37 (m, 4H), 3.55-3.70 (m, 7H), 6.07 (s, 1H),6.12 (s, 1H), 7.10-7.19 (m, 2H), 7.92-8.10 (m, 2H) ppm. MS -CI/EIm/z=473 [C₂₄H₂₇BrFN₃O+H]

Example 2774-((6bR,10aR)-5-methoxy-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

The title compound (2.0 mg, 52%) was obtained from the alkylation of theoptically pure(6bR,10aR)-5-methoxy-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride (4.2 mg) with 4-chloro-4′-fluorobutyrophenone (5.0 equiv)using the general procedure described in Example 276. ¹H NMR (CDCl₃, 300MHz) δ 1.42-1.79 (m, 4H), 1.92-2.50 (m, 4H), 2.66-2.79 (m, 2H), 286 (s,3H), 3.07-3.32 (m, 4H), 3.55-3.75 (m, 7H), 6.07 (s, 1H), 6.12(s, 1H),7.06-7.21 (m, 2H), 7.92-8.10 (m, 2H) ppm. MS-CI/EI m/z=424[C₂₅H₃₀FN₃O₂+H]

Example 278(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indolehydrochloride

Step A:

To a solution of tert-butyl6-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (15.6 g,49.15 mmol) in ethanol (250 mL) was added a spatula tip of 10% Pd/C. Thereaction mixture was shaken under a hydrogen atmosphere (15 psi, Parrapparatus) for 2 h. Upon removal from the Parr apparatus, the reactionmixture was filtered through Celite. The Celite was washed with ethanoland the combined filtrates were concentrated in vacuo to give tert-butyl6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate,quantitatively as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 1.42-1.67 (m,9H), 2.74-2.85 (m, 2H), 3.58 (brs, 2H), 3.79 (brs, 2H), 4.60 (brs, 2H),6.53-6.56 (m, 1H), 6.89-6.99 (m, 2H), 7.77 (brs, 1H) ppm.

Step B:

To a solution of tert-butyl6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4.62 g,16.08 mmol) in benzene (100 mL) was added a catalytic amount of DMAP. Aninert atmosphere was created and chloropropionyl chloride (2)(1.68 mL)was added dropwise to the reaction mixture. After stirring at roomtemperature for 20 min, the reaction mixture was transferred to aseparatory funnel containing 50% solution of sodium bicarbonate and wasextracted with CH₂Cl₂ (3×250 mL). The combined organics were dried overNa₂SO₄ and concentrated in vacuo to give tert-butyl6-[(3-chloropropanoyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylateas a white solid in 99% yield: ¹H NMR (DMSO, 500 MHz) δ 1.38-1.53 (m,9H), 2.75-2.99 (m, 2H), 3.65-3.78 (m, 4H), 3.88-3.97 (m, 2H), 4.53 (brs,2H), 6.88-6.96 (m, 1H), 7.15-7.22 (m, 1H), 7.31-7.37 (m, 1H), 9.72 (brs,1H), 10.44 (brs, 1H) ppm.

Step C:

To a suspension of NaH (95%) (100 mg, 3.96 mmol) in DMF ( 4 mL),stirring under an N₂ atmosphere at 0° C., was added dropwise a solutionof tert-butyl 6-[(3-chloropropanoyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (500 mg,1.32 mmol) and TBAI (cat.) in DMF (4 mL). The reaction was heated to 70°C. for 6 h then stirred at room temperature for 14 h. The mixture wasquenched by slow transfer of the reaction mixture to a separatory funnelcontaining a saturated solution of sodium bicarbonate. The mixture wasextracted with Et₂O (3×25 mL). The combined organics were concentratedin vacuo and the resulting residue was recrystallized from CH₃CN to givetert-butyl5-oxo-4,5,6,7,9,12-hexahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(10H)-carboxylate:¹H NMR (CDCl₃, 500 MHz) δ 1.49 (brs, 9H), 2.78 (brs, 2H), 3.02-3.07 (m,2H), 3,84 (brs, 2H), 4.24-4.28 (m, 2H), 4.62 (brs, 2H), 6.66 (d, 1H,J=7.9 Hz), 7.02 (t, 1H, J=7.9 Hz), 7.19 (d, 1H, J=7.9 Hz), 7.80 (brs,1H) ppm.

Step D:

To a solution of tert-butyl5-oxo-4,5,6,7,9,12-hexahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(10H)-carboxylate(914 mg, 2.68 mmols) in TFA (25 mL) stirring at −20° C. was addedNaCNBH₃ (675 mg, 10.71 mmols) in 5 portions. The reaction was thenstirred at −10° C. for 2 h. The yellow reaction solution was quenched bythe dropwise addition of 6 N HCl (50 mL) followed by refluxing for 35min . After cooling to room temperature, the reaction mixture was madebasic by slowly pouring it into a solution of K₂CO₃. The mixture wastransferred to a separatory funnel and extracted with CH₂Cl₂ (3×250 mL).The combined organics were dried over Na₂SO₄ and concentrated in vacuoand purified by column chromatography to give tert-butyl(8aS,12aR)-5-oxo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-]pyrido[4,3-b]indole-11(8aH)-carboxylate. ¹H NMR(CDCl₃, 300 MHz) δ 1.49 (brs, 9H), 1.81-1.94 (m, 2H), 2.77-3.94 (m,10H), 6.58-6.69 (m, 2H), 6.83 (d, 1H, J=6.7 Hz), 7.87 (s, 1H) ppm.

Step E:

To a solution of tert-butyl(8aS,12aR)-5-oxo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(449 mg, 1.31 mmols) in DMF (6 mL1), stirring under a N₂ atmosphere at−10° C., was added N-bromosuccinimide (243 mg, 1.37 mmols). After 1 h,the brominated compound was precipitated by the addition of crushed ice.The reaction mixture was allowed to warm to room temperature and thesolid collected by vacuum filtration. The white solid was washed withH₂O at 0° C. and dried under vacuum to give tert-butyl (8aS,12aR)-2-bromo-5-oxo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylatein 65% yield: ¹H NMR (CDCl₃, 500 MHz) δ 1.40-1.53 (m, 9H), 1.80-1.94 (m,2H), 2.76-2,92 (m, 2H), 3.19-3.89 ( m, 8H), 6.71 (s, 1H), 6.93 (s, 1H),7.35 (brs, 1H) ppm.

Step F:

General lactam reduction procedure: To a solution of the lactam (approx100 mg) in THF (5.0 mL), BH₃-THF (1M in THF) (4 equivs) is addeddropwise. After addition is complete, the resulting reaction mixture isrefluxed for 4 h, cooled to room temperature, and quenched cautiouslywith water (1.0 mL). The mixture is evaporated to dryness under reducedpressure and the residue obtained is treated with o-xylene (10 mL) and1-octene (5 mL) and heated at reflux for 4 h. The reaction mixture iscooled to room temperature and concentrated to dryness under reducedpressure to give the desired target as a solid.

Tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(188 mg, 100%) was prepared from the reduction of tert-butyl (8aS,12aR)-2-bromo-5-oxo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylatefrom Step E (179 mg, 0.82 mmol) using the procedure illustrated above.1H NMR (CDCl₃, 500 MHz) δ0.85-0.95 (m, 2H), 1.30-1.62 (m, 9H), 1.76-2.01(m, 3H), 2.32-2.46 (m, 1H), 2.77-2.84 (m, 1H), 3.32-3.49 (m, 4H),3.56-3.98 (m, 3H), 6.64 (s, 1H), 6.72 (s,1H) ppm.

Step G:

Tert-butyl (8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(48 mg, 42%) was prepared via coupling of tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(85 mg, 0.21 mmol) with 2,4-dichlorophenyl boronic acid (60 mg, 0.31mmol) as illustrated by the general procedure described in Example275Step A. This material was used without further purification in thesubsequent step. tert-butyl (8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(35 mg) was deprotected using the procedure described in Example 275Step B to afford the title compound (20 mg, 63%). ¹H NMR (DMSO, 500 MHz)δ 1.59-1.76 (m, 1H), 1.79-2.78 (m, 4H), 2.81-5.0 (m, 9H), 6.82-7.20 (m,2H), 7.32-7.44 (m, 1H), 7.47-7.53 (m, 1H), 7.65-7.75 (m, 1H), 8.81-9.23(m, 2H) ppm. MS-CI; m/z=376[C₂₀H₂₁Cl₂N₃+H]⁺.

Example 279(8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole hydrochloride

Tert-butyl (8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(48 mg, 52%) was prepared via coupling of the tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(85 mg, 0.21 mmol) with 2-methyl-4-methoxyphenyl boronic acid (53 mg,0.31 mmol) using the general procedure described in Example275 Step A.This material was used without further purification in the subsequentstep.

Tert-butyl (8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(38 mg) was deprotected using the procedure described in Example 275Step B to afford the title compound (22 mg, 61%). ¹H NMR (DMSO, 500 MHz)δ 1.86-1.97 (m, 1H), 2.07-2.18 (m, 2H), 2.22 (s, 3H), 2.35-2.48 (m, 2H),2.62-2.70 (m, 1H), 2.86-2.93 (m, 1H), 3.17-3.71 (m, 9H), 3.79 (s, 3H),6.71-6.82 (m, 4H), 7.02-7.07 (m, 1H) ppm. MS-CI; m/z=350[C₂₂H₂₇N₃O+H]^(+.)

Example 280(8aS,12aR)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indol-5(4H)-onehydrochloride

Tert-butyl (8aS,12aR)-2-(2,4-dichlorophenyl)-4-methyl-5-oxo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(223 mg, 48%) was prepared via coupling of tert-butyl (8aS,12aR)-2-bromo-4-methyl-5-oxo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(404 mg, 0.96 mmol) with 2,4-dichlorophenyl boronic acid (275 mg, 1.44mmol) using the general procedure described in Example 275 Step A. ¹HNMR (CDCl₃, 500 MHz) δ 1.41 (brs, 9H), 1.85-1.98 (m, 2H) 2.83-2.96 (m,2H) , 3.18-3.46 (m, 4H) , 3.46-3.54 (m, 2H), 3.76 (d, 1H, J=1.6 Hz),3.83 (brs, 1H), 6.63 (s, 1H), 6.92 (s, 1H), 7.18-7.27 (m, 2H), 7.39 (s,1H), 7.45 (s, 1H)

Tert-butyl (8aS,12aR)-2-(2,4-dichlorophenyl)-4-methyl-5-oxo-4,5,6,7,9,10,12,12a-octahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate(75 mg) was deprotected using the procedure described in Example 275Step B to afford the title compound. (52 mg, 83%) ¹H NMR (CD3OD, 300MHz) δ 2.06-2.19 (m, 1H), 2.27-2.36 (m, 1H), 2.80-2.92 (m, 4H),3.16-3.34 (m, 3H), 3.37-3.59 (m, 4H), 3.68-3.74 (m, 1H), 6.94 (d, 1H,J=3.3 Hz), 7.04 (d, 1H, J=3.3 Hz), 7.29-7.38 (m 2H), 7.53 (d, 1H, J=1.7Hz) ppm. MS-CI; m/z 389 [C₂₀H₁₉Cl₂N₃O+H]⁺.

Example 281(6bS,11aS)-3-methyl-2,3,7,8,9,10,11,11a-octahydro-1-H,6bH-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]uinoxaline

Step A:

o-Nitrophenyl hydrazine (5.22 g, 34 mmol) and azepin-3-one 2 (5.09 g, 34mmol) were dissolved in 60 mL of CF₃CH₂OH. The solution was refluxed for1 hr. The reaction was cooled to rt and concentrated. The organic solidwas transferred to a sealed tube, and 100 mL of conc HCl were added. Themixture was heated to 80° C. for 18 hrs. The reaction was then cooled to0° C. and ice chips were added to the reaction vessel. The reaction wasbasified with 50% NaOH until the pH=14. Dioxane (100 mL) and Boc2O (8.18g, 3.7 mmol) were added. This solution was stirred at rt for 18 hrs. Thereaction was then concentrated. Brine (50 mL) and CHCl₃ were added tothe residue and the biphasic mixture was stirred for 10 min. The layerswere separated, and the aqueous phase was re-extracted with CHCl₃ (2×30mL). The combined organic layers were washed with brine, dried, andconcentrated to afford 7.8 g of a brown residue. This crude product waspurified by column chromatography (1-2% MeOH/CH₂Cl₂) to affordtert-butyl7-nitro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (5.87g, 52%) as an amorphous solid. ¹H NMR (CDCl₃, 300 MHz) δ 9.45 (1H, bs),8.07 (1H, bd, J=8.1 Hz), 7.7-7.9 (1H, m), 7.13-7.19 (1H, m), 3.69-3.73(4H, m), 2.9-3.11 (4H, m), 1.50 (9H, s) ppm.

Step B:

NaH was suspended in DMF (2 mL) at 0° C. tert-butyl7-nitro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (462mg, 1.4 mmol) was added as a solution in DMF (4mL) drop-wise. Thereaction was heated to 40° C. for 10 min was the cooled back to 0° C.Bromoethyl acetate was added drop-wise. The reaction was warmed to rtand stirred for 3 hrs. Brine (20 mL) and EtOAc (20 mL) were added to thereaction and stirred for 10 min. The layers were separated. The aqueouslayer was re-extracted with EtOAc (2×20 mL). The combined organic layerswere washed with brine, dried, and concentrated to afford 498 mg of abrown viscous oil. This crude product was purified by columnchromatography (30% EtOAc/hexane) to afford tert-butyl6-(2-ethoxy-2-oxoethyl)-7-nitro-1,4,5,6-tetrahydroazpino[4,5-b]indole-3(2H)-carboxylateas an orange amorphous solid (453 mg, 53%). ¹H NMR (CDCl₃, 300 MHz) δ7.80 (1H, d, J=7.7 Hz), 7.10-7.75 (1H, m), 7.11-7.16 (1H, m), 4.82 (2H,s), 4.25 (2H, q, J=7.0 Hz), 3.6-3.9 (4H, m), 2.8-3.1 (4H, m), 1.48 (9H,s), 1.30 (3H, t, J=7.0 Hz) ppm.

Step C:

Tert-butyl6-(2-ethoxy-2-oxoethyl)-7-nitro-1,4,5,6-tetrahydroazpino[4,5-b]indole-3(2H)-carboxylate(146 mg, 0.35 mmol) was added to EtOH (15 mL). The reaction flask wasevacuated and shaken on a Parr shaker at 55 psi of H₂. After 18 hrs, thereaction was disassembled and was filtered over a cake of Celite. Thesupernatant was concentrated to afford 115 mg of a black material, whichwas purified by column chromatography. tert-butyl2-oxo-2,3,7,8,10,11-hexahydro-1H,9H-azepino[4′5′:4,5]pyrrolo[1,2,3-de]quinoxaline-9-carboxylate(93.6 mg, 78%) was isolated as a white amorphous solid. ¹H NMR (CDCl₃,300 MHz) δ 7.96 (1H, bs), 7.11-7.17 (1H, m), 6.92-6.98 (1H, s), 6.50(1H, s), 4.86 (2H, s), 3,68-3.73 (4H, m), 2.91-3.05 (4H, m) 1.59 (9H, s)ppm.

Step D:

Tert-butyl2-oxo-2,3,7,8,10,11-hexahydro-1H,9H-azepino[4′5′:4,5]pyrrolo[1,2,3-de]quinoxaline-9-carboxylate(501.4 mg, 1.5 mmol) was dissolved in DMF (5mL). The solution was cooledto 0° C. NaH (44.5 mg, 1.76 mmol) was added. The reaction was warmed to50° C. for 45 min. The reaction was cooled back to 0° C., and excess MeIwas added. The reaction was then stirred at 0° C. for 2 hrs. Thereaction was quenched with a saturated aqueous solution of NH₄Cl. Thereaction was extracted with EtOAc (3×15 mL). The combined organic layerswere washed with brine, dried, and concentrated to afford 558 mg of abrown oil. This crude product was purified by column chromatography(2-5% MeOH/CH₂Cl₂) to afford tert-butyl3-methyl-2-oxo-2,3,7,8,10,11-hexahydro-1H,9H-azepino[4′5′:4,5]pyrrolo[1,2,3-de]quinoxaline-9-carboxylate(152.9 mg, 29%) as a white amorphous solid. ¹H NMR (CDCl₃, 300 MHz) δ7.14-7.18 (1H, m), 6.99-7.04 (1H, m), 6.63 (1H, d, J=7.3 Hz), 4.88 (2H,s), 3.63-3.74 (4H, m), 3.46 (3H, s), 2.89-2.99 (4H, m), 1.59 (9H, m)ppm.

Step E:

Tert-butyl3-methyl-2-oxo-2,3,7,8,10,11-hexahydro-1H,9H-azepino[4′5′:4,5]pyrrolo[1,2,3-de]quinoxaline-9-carboxylate(153.3 mg, 0.6 mmol) was dissolved in THF (20 mL). 1M BH₃THF (2.1 mL,2.1 mmol) was added drop-wise. The reaction was refluxed for 2 hours andthen subsequently cooled to rt. 5M HCl (12 mL) was added drop-wise.After the bubbling ceased, the reaction was heated to reflux for 30 min,after which it was cooled to 0° C. 50% NaOH was added drop-wise untilthe pH=14. The reaction mixture was extracted with CHCl₃ (3×20 mL). Thecombined organic layers were washed with brine, dried, and concentratedto afford a 190 mg light-brown oil. This crude material was dissolved indioxane (4 mL) and 1M NaOH (2mL), and then BOc₂O (143 mg, 6.6 mmol) wasadded. The solution was stirred for 18 hrs, and then it wasconcentrated. EtOAc (20 mL) and brine (20 mL) were added to the residueand stirred for 10 min. The layers were separated, and the aqueous wasre-extracted with EtOAc (2×20 mL). The combined organic layers werewashed with brine, dried, and concentrated to afford 220 mg of a brownoil. This crude product was purified by column chromatography (30%acetone/hexane) to afford (120 mg, 58%) of tert-butyl(6bS,11aS)-3-methyl-2,3,6b,7,8,10,11,11a-octahydro-1H,9H-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline-9-carboxylateas a clear oil. ¹H NMR (CDCl₃, 300 MHz) δ 6.55-6.7 (1H, m), 6.4-6.5 (1H,m), 6.37 (1H, d, J=7.7 Hz), 3.1-3.7 (9H, m), 3.8-3.9 (4H, m), 1.7-2.1(4H, m), 1.46 (9H, s) ppm.

Step F:

Tert-butyl(6bS,11aS)-3-methyl-2,3,6b,7,8,10,11,11a-octahydro-1H,9H-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline-9-carboxylate(115 mg, 0.33 mmol) was dissolved in 20% TFA (3 mL) in CH₂Cl₂ at rt. Thereaction was stirred at rt for 2.5 hrs. Ice chips were added to thereaction, an then it was basified with 50% NaOH until pH=14. Brine (5mL) was added and then the reaction was extracted with CH₂Cl₂ (2×10 mL).The combined organic layers were washed with brine, dried, andconcentrated to afford the title compound (84.1 mg, 103%) as a viscousoil. ¹H NMR (CDCl₃, 300 MHz) δ 6.59-6.64 (1H, m), 6.48 (1H, d, J=7.3Hz), 6.37 (1H, d, J=7.7 Hz), 3.4-3.7 (4H, m), 2.6-3.3 (10H, m), 1.7-2.2(4H, m) ppm. MS (ESI): 244.2 (base, M+H)

Example 2824-(3-methyl-2,3,6b,7,8,10,11,11a-octahydro-1H,9H-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxalin-9-yl)-1-(4-fluorophenyl)-1-butanone

3-Methyl-2,3,7,8,9,10,11,11a-octahydro-1H,6bH-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline(72 mg, 0.3 mmol), 4-chloro-4′-flourobutyrophenone (119 mg, 0.6 mmol),KI (49 mg, 0.3 mmol), and DIEA (383 mg, 3 mmol) were added to dioxane(2.5 mL). The suspension was stirred at 96° C. for 18 hrs. The reactionwas cooled to rt and then concentrated. The residue was purified bycolumn chromatography (5-10 % MeOH/CH₂Cl₂), to afford the title compound(37.5 mg, 31%) as an oil. The enantiomers of the title compound wereseparated on a Chiracel OD column using 8% EtOH-Hexane as the eluent. 1HNMR (CDCl₃, 300 MHz) δ 7.9-8.1 (2H, m), 7.1-7.2 (2H, m), 6.6-6.7 (1H,m), 6.3-6.5 (2H, m), 2.7-3.8 (19 H, m), 1.9-2.3 (4H, m) ppm. MS (ESI):408.3 (base, M+H)

Example 283(+/−)-1,1,3-Trimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Step A:

To a solution of ethyl2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(from Example 211, Step A) (360 mg, 1.2 mmol) in DMF (20 mL) at rt wasadded NaH (172 mg, 4.8 mmol), MeI (0.25 mL, 4.0 mmol) and stirred at 25°C. for 6 hours. The solution was diluted with water (30 mL) andextracted with EtOAc (2×30 mL). The combined extracts were dried overmagnesium sulfate, concentrated, and purified by flash chromatography toafford ethyl1,1,3-trimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(370 mg, 90%) as an oil. MS [M+H]⁺342. ¹H NMR (CDCl₃, 300 MHz): δ 7.12(d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.63 (d, 1H, J=7.7 Hz), 4.69(s, 2H), 4.23 (m, 2H), 3.86 (m, 2H), 3.43 (s, 3H), 3.01 (m, 2H), 1.81(s, 6H), 1.24 (t, 3H, J=7.3 Hz) ppm.

Step B:

To a solution of ethyl1,1,3-trimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(240 mg, 0.7 mmol) in THF (20 mL) at 25° C. was added BH₃/THF complex(0.7 mL, 0.7 mmol). The mixture was stirred at 80° C. for 5 hours thencooled to rt and added 6N HCl (10 mL) with stirred for another 1 hr.About 30 mL of H₂O was added and then was extracted with EtOAc (2×30mL). The combined extracts were dried over magnesium sulfate,concentrated, and purified by flash chromatography to giveethyl-1,1,3-trimethyl-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylateas an oil (152 mg, 66%). MS [M+H]⁺327. ¹H NMR (CDCl₃, 300 MHz) δ 7.01(t, 1H, J=7.7 Hz), 6:97 (d, 1H, J=7.7 Hz), 6.41 (d, 1H, J=7.7 Hz), 4.68(s, 2H), 4.23 (m, 2H), 3.84 (m, 2H), 3.11 (m, 2H), 2.99 (s, 3H), 1.54(s, 6H), 1.27 (t, 3H, J=7.3 Hz) ppm.

Step C:

To a solution ofethyl-1,1,3-trimethyl-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(69 mg, 0.21 mmol) in TFA (2 mL) at 0° C. was added NaBH₃CN (53 mg, 0.84mmol). The mixture was stirred at rt for 4 hours, and then removed theTFA by N₂. About 10 mL of H₂O was added and then was extracted withEtOAc (2×10 mL). The combined extracts were dried over magnesium sulfateand concentrated to affordethyl-1,1,3-trimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylateas an oil which was used for the next reaction (45 mg, 65%). MS[M+H]+330.

Step D:

To a solution of ethyl 1,1,3-trimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(8 mg, 0.02 mmol) in n-butanol (5 mL) at rt was added KOH (50 mg, 0.89mmol) and stirred at 120° C. for 20 hours. The solution was diluted withwater (10 mL) and extracted with EtOAc (2×20 mL). The combined extractswere dried over magnesium sulfate and concentrated to afford the titlecompound (5 mg, 81%). MS [M+H]+258.

Example 284(+/−)-1-(4-Fluorophenyl)-4-(1,1,3-trimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-butanone

To a solution of1,1,3-trimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline(from Example 283) (82 mg, 0.32 mmol) in dioxane (10 mL) at rt was added4-chloro-1-(4-fluorophenyl)butan-1-one (83 mg, 0.42 mmol), K₂CO₃ (100mg), KI (30 mg) and stirred at 25° C. for 24 hours. The solution wasdiluted with water (30 mL) and extracted with EtOAc (2×30 mL). Thecombined extracts were dried over magnesium sulfate, concentrated, andpurified by flash chromatography to afford the title compound (58 mg,43%). MS [M+H]+422. ¹H NMR (CDCl₃, 300 MHz): δ 8.01 (m, 2H) , 7.15 (t,2H, J=7.7 Hz), 6.65 (t, 1H, J=7.7 Hz), 6.51 (d, 1H, J=7.0 Hz), 6.43 (d,1H, J=7.0 Hz), 3.63 (m, 1H), 3.25 (d, 1H, J=11 Hz), 3.09 (m, 2H), 2.89(s, 3H), 2.63 (m, 2H), 2.25 (m, 2H), 2.17 (m, 2H), 1.31 (s, 3H), 1.12(s, 3H) ppm. This racemate was then separated into its correspondingenantiomers by HPLC utilizing a Chiralcel AD column with 50%Ethanol/Methanol solvent system.

Example 285(+/−)-1,3-Dimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Step A:

To a solution of ethyl2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(from Example 211, StepA) (500 mg, 1.6 mmol) in DMF (20 mL) at rt wasadded NaH (147 mg, 3.6 mmol), MeI (0.25 mL, 4.0 mmol) and stirred at 25°C. for 3 hours. The solution was diluted with water (30 mL) andextracted with EtOAc (2×30 mL). The combined extracts were dried overmagnesium sulfate, concentrated, and purified by flash chromatography toafford ethyl1,3-dimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate(350 mg, 64%) as an oil. MS [M+H]⁺328. ¹H NMR (CDCl₃, 300 MHz): δ 7.18(d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.63 (d, 1H, J=7.7 Hz), 4.90(m, 1H), 4.51 (m, 1H), 3.20 (m, 5H), 3.49 (m, 1H), 3.42 (s, 3H), 2.91(m, 1H), 2.80 (m, 1H), 1.61 (d, 3H, J=7.0), 1.28 (t, 3H, J=7.3 Hz) ppm.

Step B:

Following the procedure of example 283 Steps B-D to afford the titlecompound. MS [M+H]⁺258.

Example 2864-(1,3-Dimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

The title compound was prepared in a manner similar to that describedfor Example 284, utilizing1,3-dimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinefrom Example 285. The product was obtained as colorless oil. MS[M+H]⁺408. ¹H NMR (CDCl₃, 300 MHz): δ 7.89 (m, 2H), 7.15 (t, 2H, J=8.4Hz), 6.62 (t, 1H, J=7.3 Hz), 6.51 (d, 1H, J=7.4 Hz), 6.39 (d, 1H, J=7.4Hz), 3.63 (m, 1H), 3.52 (m, 4H), 3.15 (m, 4H), 3.86 (s, 3H), 3.65 (m,4H), 2.17 (m, 2H), 1.81 (m, 1H), 1.21 (m, 1H), 1.13 (d, 3H, J=6.2 Hz)ppm. This racemate was then separated into its corresponding enantiomersby HPLC utilizing a Chiralcel AD column with 90% Acetonitrile/2-Propanolsolvent system.

Example 2874-(1,3-dimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone

The title compound was prepared in a manner similar to that describedfor Example 284, utilizing1,3-dimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinefrom Example 285. The product was obtained as colorless oil. MS[M+H]⁺408. ¹H NMR (CDCl₃, 300 MHz): δ 8.00 (m, 2H), 7.15 (m, 2H), 6.62(t, 1H, J=7.3 Hz), 6.51 (d, 1H, J=7.4 Hz), 6.39 (d, 1H, J=7.4 Hz), 3.63(t, 1H, J=5.2 Hz), 3.60 (m, 1H), 3.40 (m, 4H), 3.25 (m, 4H), 2.82 (s,3H), 2.60 (m, 4H), 2.17 (m, 2H), 1.81 (m, 1H), 1.13 (d, 3H, J=6.2 Hz)ppm. This racemate was then separated into its corresponding enantiomersby HPLC utilizing a Chiralcel AD column with 90% Acetonitrile/2-Propanolsolvent system.

Example 288(+/−)-5-(2,4-dichlorophenyl)-2-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

Step A:

To a solution of tert-butyl6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (7 g,24.3 mmol) in CH₂Cl₂ (40 mL) at rt was added saturated K₂CO₃ (30 mL),ethyl chloroformate (2.4 mL, 4.0 mmol) and stirred at 25° C. for 0.5hour. The solution was diluted with water (30 mL) and extracted withCH₂Cl₂ (2×30 mL). The combined extracts were dried over magnesiumsulfate, and concentrated to afford tert-butyl6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate(8.7 g, 100%) as an crude oil. MS [M+H]⁺360.

Step B:

To a solution of tert-butyl6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate(8.7 g, 24.3 mmol) in CH₂Cl₂ (40 mL) at rt was added TFA (20 mL) andstirred at rt for 3 hours before the solvent was removed by the nitrogenstream. The solution was diluted with water (30 mL) and extracted withCH₂Cl₂ (2×30 mL). The combined extracts were dried over magnesiumsulfate, and concentrated to afford an crude residue that wasre-dissolved in CH₂Cl₂ (40 mL) followed by saturated K₂CO₃ (30 mL),ethyl chloroformate (2.4 mL, 4.0 mmol) and stirred at 25° C. for 0.5hour. The solution was diluted with water (30 mL) and extracted withCH₂Cl₂ (2×30 mL). The combined extracts were dried over magnesiumsulfate, concentrated, and purified by flash chromatography to affordethyl6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate(4.5 g, 67%) as a clear oil. MS [M+H]⁺332. ¹H NMR (CDCl₃, 300 MHz): δ7.00 (t, 1H, J=7.7 Hz), 6.82 (m, 1H), 6.71 (m, 1H), 4.62 (s, 2H),4.02-4.31 (m, 4H), 3.82 (t, 1H, J=5.5 Hz), 2.82 (t, 1H, J=5.5 Hz),1.20-1.24 (m, 6H) ppm.

Step C:

To a solution of ethyl6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4.5 g, 13.6 mmol) in CH₂Cl₂ (40 mL) at 0° C. wasadded TFA (20 mL) followed by NaCNBH₃ (1.8 g, 27 mmol) and stirred at rtfor 3 hours before the solvent was removed by the nitrogen stream. Tothe resulting residue were added CH₂Cl₂ (40 mL) and 6N HCl (20 mL) andstirred for 0.5 hour. The solution was diluted with water (20 mL), 1NNaOH (30 mL) and extracted with CH₂Cl₂ (2×30 mL). The combined extractswere dried over magnesium sulfate, concentrated, and purified by flashchromatography to afford ethyl6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate(3.6 g, 80%) as a clear oil. MS [M+H]⁺334. ¹H NMR (CDCl₃, 300 MHz): δ6.97 (d, 1H, J=7.3 Hz), 6.85 (d, 1H, J=7.3 Hz), 6.72 (t, 1H, J=7.3 Hz),4.05 (m, 4H), 3.41 (m, 4H), 1.92 (m, 2H), 1.20-1.24 (m, 6H) ppm.

Step D:

To a solution of ethyl6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate(2.2 g, 6.6 mmol) in DMF (20 mL) at 0° C. was added NaH (660 mg, 16.5mmol), DMAP (878 mg, 7.2 mmol), acetyl chloride (0.6 mL, 7.2 mmol) andstirred at rt for 16 hours. The solution was diluted with water (30 mL),and extracted with EtOAc (2×30 mL). The combined extracts were driedover magnesium sulfate, concentrated, and purified by flashchromatography to afford diethyl1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(1.1 g, 57%) as a clear oil. MS [M+H]⁺374. ¹H NMR (CDCl₃, 300 MHz): δ6.75 (t, 1H, J=7.7 Hz), 6.59 (m, 1H), 6.45 (m, 1H), 4.05 (m, 1H),3.60-4.00 (m, 7H), 3.40 (m, 1H), 3.00 (m, 3H), 1.92 (m, 2H), 0.91 (m,1H), 0.85 (m, 6H) ppm.

Step E:

To a solution of diethyl1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(360 mg, 0.97 mmol) in DMF (20 mL) at 0° C. was added NaH (193 mg, 4.8mmol), MeI (0.3 mL, 4.8 mmol)- and stirred at rt for 16 hours. Thesolution was diluted with water (20 mL), and extracted with EtOAc (2×20mL). The combined extracts were dried over magnesium sulfate,concentrated to afford diethyl2-methyl-1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(300 mg, 80%) as a crude oil. MS [M+H]⁺388.

Step F:

To a solution of diethyl2-methyl-1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(300 mg, 0.77 mmol) in THF (10 mL) at rt was added BH₃THF complex (3.8mL, 3.8 mmol) and refluxed for 5 hours. At rt 6N HCl (10 mL) was addedand stirred for 0.5 hour before the solution was diluted with water (20mL), and extracted with EtOAc (2×20 mL). The combined extracts weredried over magnesium sulfate, concentrated, and purified by flashchromatography to afford diethyl2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(200 mg, 69%) as a clear oil. MS [M+H]⁺374.

Step G:

To a solution of diethyl2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(40 mg, 0.1 mmol) in DMF (10 mL) at 0° C. was added NBS (20 mg, 0.11mmol) and stirred at 0° C. for 2 hours. The solution was diluted withwater (10 mL), and extracted with EtOAc (2×20 mL). The combined extractswere dried over magnesium sulfate, concentrated, and purified by flashchromatography to afford diethyl5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(40 mg, 88%) as a clear oil. MS [M+H]⁺454.

Step H:

To a solution of diethyl5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(100 mg, 0.22 mmol) in DMF (10 mL) was added 2,4-dichlorophenyl boronicacid (63 mg, 0.33 mmol) and Na₂CO₃ (58 mg, 0.55 mmol, in 0.4 mL of H₂O).The mixture was degassed with a stream of nitrogen for 20 min and thenthere was added Pd(PPh₃)₄ (35 mg, 0.03 mmol) and the mixture was stirredat 100° C. for 16 h. The reaction was allowed to cool to ambienttemperature and was diluted with ethyl acetate, washed with saturatedaqueous sodium bicarbonate and brine, dried (MgSO₄), filtered throughCelite and concentrated in vacuo. The residue was purified by flashchromatography (elution with hexanes/ethyl acetate) to afford diethyl5-(2,4-dichlorophenyl)-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(30 mg, 29% yield) MS [M+H]+517.

Step I:

To a solution of diethyl5-(2,4-dichlorophenyl)-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate(30 mg, 0.06 mmol) in 10 mL of n-BuOH was added KOH (33 mg, 0.6 mmol)and stirred at 120° C. for 16 h. The reaction was allowed to cool toambient temperature and was diluted with ethyl acetate, washed withwater (10 mL). The organic layer was collected and washed with 1N HCl(10 mL) and water (10 mL). This time the aqueous layer was collected andneutralized with saturated aqueous sodium bicarbonate and extracted withEtOAc (2×20 mL). The combined extracts were dried over magnesiumsulfate, concentrated to afford5-(2,4-dichlorophenyl)-2-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline(10 mg, 45%) as a solid. MS [M+H]⁺374.

Utility

The compounds of the present invention have therapeutic utility forillnesses or disorders involving the neurotransmitter serotonin(5-hydroxy tryptamine or 5-HT) and either agonism or antagonism of 5-HT2receptors, as demonstrated by the assays described below. Therapeuticutility for these illnesses or disorders could involve numerousbiological processes affected by serotonin including, but not limitedto, appetite, mood, sleep, sexual activity, and arterial constriction.These biological processes may also be important to numerous centralnervous system (CNS) disorders including those related to the affectivedisorders of depression, anxiety, psychosis, and schizophrenia, as wellas, disorders of food intake such as anorexia, bulemia, and obesity. Thecompounds of the present invention potentially have therapeutic utilityin other conditions in which serotonin has been implicated, such asmigraine, attention deficit disorder or attention deficit hyperactivitydisorder, addictive behavior, and obsessive-compulsive disorder, as wellas, conditions associated with cephalic pain, social phobias, andgastrointestinal disorders such as dysfunction of the gastrointestinaltract motility. Lastly, compounds of the present invention potentiallyhave therapeutic utility in neurodegenerative diseases and traumaticconditions represented by the examples of Alzheimer's disease andbrain/spinal cord trauma.

The pharmacological analysis of each compound for either antogonism oragonism of at 5-HT2A and 5-HT2C receptors consisted of in vitro and invivo studies. In vitro analyses included Ki determinations at 5-HT2A and5-HT2C receptors and an assessment of functional (i.e., agonism orantagonism) activity at each receptor class by IP3 hydrolysis assays.Additional receptor assays were conducted to evaluate receptorspecificity of 5-HT2A and 5-HT2C receptors over monoamine and nuisancereceptors (e.g. histamine, dopamine, and muscarinic). A compound isconsidered active as a 5-HT2A antagonist or a 5-HT2C agonist if it hasan IC₅₀ value or a K_(i) value of less than about 1 micromolar;preferably less than about 0.1 micromolar; more preferably less thanabout 0.01 micromolar. Compounds of the invention have been shown tohave an IC₅₀ value of less than about 1 micromolar for 5-HT2A antagonismor a 5-HT2C agonism.

In vivo assays assessed compound activity in a variety of behavioralparadigms including quipazine head twitch, acute and chronic feedingmodels, anxiety and depression models (learned-helplessness, elevatedplus maze, Geller-Siefter, conditioned taste aversion, taste reactivity,satiety sequence). In aggregate, these models reflect activity as a5-HT2A antagonist (quipazine head twitch, depression models) or 5-HT2Cagonist (feeding models, anxiety models, depression models) and providesome indication as to bioavailability, metabolism and pharmacokinetics.

Radioligand binding experiments were conducted on recombinant human5-HT2A and 5-HT2C receptors expressed in HEK293E cells. The affinitiesof compounds of the present invention to bind at these receptors isdetermined by their capacity to compete for[¹²⁵I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI) binding atthe 5-HT2A or 5-HT2C. General references for binding assays include 1)Lucaites V L, Nelson D L, Wainscott D B, Baez M (1996) Receptor subtypeand density determine the coupling repertoire of the 5-HT2 receptorsubfamily. Life Sci., 59(13):1081-95. J Med Chem 1988 January;31(1):5-7; 2) Glennon R A, Seggel M R, Soine W H, Herrick-Davis K, LyonR A, Titeler M (1988)[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane: an iodinatedradioligand that specifically labels the agonist high-affinity state of5-HT2 serotonin receptors. J Med. Chem. 31(1):5-7 and 3) Leonhardt S,Gorospe E, Hoffman B J, Teitler M (1992) Molecular pharmacologicaldifferences in the interaction of serotonin with 5-hydroxytryptamine1Cand 5-hydroxytryptamine2 receptors. Mol Pharmacol., 42(2):328-35.

The functional properties of compounds (efficacy and potency) weredetermined in whole cells expressing 5-HT2A or 5-HT2C receptors byassessing their ability to stimulate or inhibit receptor-mediatedphosphoinositol hydrolysis. The procedures used are described below.

In Vitro Binding Assays Stable Expression of 5-HT2A and 5-HT2C Receptorsin HEK293E Cells

Stable cell lines were generated by transfecting 293EBNA cells withplasmids containing human 5-HT2A , 5-HT2B, or 5-HT2C (VNV editedisoform) cDNA using calcium phosphate. These plasmids also contained thecytomegalovirus (CMV) immediate early promoter to drive receptorexpression and EBV or iP for their maintenance as an extrachromosomalelement, and the hph gene from E. Coli to yield hygromycin B resistance(Horlick et al., 1997). Transfected cells were maintained in Dulbecco'sModified Eagle medium (DMEM) containing dialyzed 10% fetal bovine serumat 37° C. in a humid environment (5% CO₂) for 10 days. The 5-HT2A cellswere adapted to spinner culture for bulk processing whereas it wasnecessary to maintain the other lines as adherent cultures. On the dayof harvest, cells were washed in phosphate-buffered saline (PBS),counted, and stored at −80° C.

Membrane Preparation

On the day of assay, pellets of whole cells (containing approximately1×108 cells) expressing the 5-HT2A or 5-HT2C receptor were thawed on iceand homogenized in 50 mM Tris HCl (pH 7.7) containing 1.0 mM EDTA usinga Brinkman Polytron (PT-10, setting 6 for 10 sec). The homogenate wascentrifuged at 48,000×g for 10 min and the resulting pellet washed twiceby repeated homogenization and centrifugation steps. The final pelletwas resuspended in tissue buffer and protein determinations were made bythe bichichoninic acid (BCA) assay (Pierce Co., Ill.) using bovine serumalbumin as the standard. Radioligand Binding Assays for the 5-HT2A and5-HT2C Receptors

Radioligand binding studies were conducted to determine the bindingaffinities (KI values) of compounds for the human recombinant 5-HT2A,5-HT2B, and 5-HT2C receptors (Fitzgerald et al., 1999). Assays wereconducted in disposable polypropylene 96-well plates (Costar Corp.,Cambridge, Mass.) and were initiated by the addition of 5-HT2A, 5-HT2B,or 5-HT2C membrane homogenate in tissue buffer (10-30 (g/well) to assaybuffer (50 mM Tris HCl, 0.5 mM EDTA, 10 mM pargyline, 10 mM MgSO₄, 0.05% ascorbic acid, pH 7.5) containing [¹²⁵I]DOI for the 5-HT2A and 5-HT2Creceptors (0.3-0.5 nM, final) or [³H]LSD (2-2.5 nM, final) for the5-HT2B receptor, with or without competing drug (i.e, newly synthesizedchemical entity). For a typical competition experiment, a fixedconcentration of radioligand was competed with duplicate concentrationsof ligand (12 concentrations ranging from 10 picomolar to 10micromolar). The reaction mixtures were incubated to equilibrium for 45min at 37° C. and terminated by rapid filtration (cell harvestor;Inotech Biosystems Inc., Lansing, Mich.) over GFF glass-fiber filtersthat had been pre-soaked in 0.3% polyethyleneimine. Filters were washedin ice-cold 50 mM Tris HCl buffer (pH 7.5) and then counted in a gammacounter for the 5-HT2A and 5-HT2C assays, or by liquid scintillationspectroscopy for the 5-HT2B assay.

Phosphoinositide Hydrolysis Studies

The ability of newly synthesized compounds to stimulate phosphoinositide(PI) hydrolysis was monitored in whole cells using a variant (Egan etal., 1998) of a protocol described previously (Berridge et al., 1982).HEK293E cells expressing the human 5-HT2A, 5-HT2B, or 5-HT2C receptorwere lifted with 0.5 mM EDTA and plated at a density of 100,000/wellonto poly-D-lysine-coated 24-well plates (Biocoat; Becton Dickinson,Bedford, Mass.) in Dulbecco's modified Eagle's serum (DMEM; Gibco BRL)containing high glucose, 2 mM glutamine, 10% dialyzed fetal calf serum,250 (g/ml hygromycin B, and 250 (g/ml G418. Following a 24-48 hr period,the growth media was removed and replaced with DMEM without fetal calfserum and inositol (Gibco BRL). The cells were then incubated with DMEM(without serum and inositol) containing a final concentration of 0.5uCi/well myo-[³H]inositol for 16-18 hr. Following this incubation, thecells were washed with DMEM (without serum or inositol) containing 10 mMLiCl and 10 (M pargyline and then incubated for 30 min with the samemedia but now containing one of several test compounds. Reactions wereterminated by aspirating the media and lysing the cells by freeze-thaw.[³H]phosphoinositides were extracted with chloroform/methanol (1:2 v/v),separated by anion exchange chromatography (Bio-Rad AGI-X8 resin), andcounted by liquid scintillation spectroscopy as described previously(Egan et al., 1998).

Data analyses

The equilibrium apparent dissociation constants (Ki's) from thecompetition experiments were calculated using an iterative nonlinearregression curve-fitting program (GraphPad Prism; San Diego, Calif). Forthe PI hydrolysis experiments, EC50's were calculated using a one-site‘pseudo’ Hill model: y=((Rmax-Rmin)/(1+R/EC50)nH))+Rmax where R=response(DeltaGraph, Monterey, Calif.). Emax (maximal response) was derived fromthe fitted curve maxima (net IP stimulation) for each compound.Intrinsic activity (IA) was determined by expressing the Emax of acompound as a percentage of the Emax of 5-HT (IA=1.0).

In Vivo Experiments for Serotonergic Ligands

Preclinical Efficacy, Potency, and Side Effect Liability.

a) Anti-Serotonin Efficacy.

Antagonism of Quipazine-Induced Head Twitch in Rat. Quipazine, anagonist at 5-HT receptors, produces a characteristic head twitchresponse in rats. 5-HT receptor antagonists effectively antagonize this5-HT agonist-induced behavioral effect (Lucki et al., 1984).Accordingly, the quipazine-induced head twitch model in rat can functionas an in vivo behavioral correlate to 5-HT receptor binding. Compoundsare administered 30 minutes before behavioral testing (and 25 minutesbefore quipazine), and a dose-related antagonism of the quipazineresponse is determined.

b) Antipsychotic Efficacy.

Inhibition of the Conditioned Avoidance Response (CAR) in Rat. Rats aretrained to consistently avoid (by climbing onto a pole suspended fromthe ceiling of the test chamber) an electric foot shock (0.75 mA)delivered to the grid floor of the testing chamber. All antipsychoticdrugs effectively inhibit this conditioned avoidance response (Arnt,1982). The ability of a compound to inhibit this response is used todetermine the antipsychotic efficacy of potential drug candidates.

c) Extrapyramidal Side Effect Liability

Induction of Catalepsy in Rat. Typical antipsychotic drugs produceextrapyramidal side effects (EPS) at clinically effective doses. Themost widely accepted preclinical indicator of EPS liability in humans isa drug-induced catalepsy syndrome in rat (Costall and Naylor, 1975), acondition whereby the animal will remain immobile in an externallyimposed posture (analogous to a catatonic stupor in humans). Rats aretested for induction of catalepsy in a dose-response test after oraladministration of compounds.

d) CNS penetration; In vivo Brain Receptor Occupancy.

In Vivo Binding. To determine the level of in vivo receptor occupancy,an in vivo receptor binding protocol is used. This procedure uses anappropriate radioligand to label the receptor of interest. For example,to measure both Dopamine D2 and 5-HT2A receptors in vivo, one can use³H-N-methyl spiperone (³H -NMSP), (Frost, et. al. 1987) The procedureuses rats (or mice) fasted overnight. To measure the effects ofcompounds on the receptors of interest, compounds are dosed, usuallyp.o. for example in 2 microliters/gram body weight in 0.25% Methocelsuspension. The radiolabeled compound (in this example, ³H-NMSP) isadministered by i.v. tail vein injection (10 microcuries label/200 gramrat). Time course experiments are used to determine the optimal time ofbinding for both the radiolabeled and unlabeled compound. These optimaltime frames are used for all subsequent dose-response experiments. Afterthe appropriate time frame of compound/radioligand exposure, the animalsare sacrificed and the relevant brain regions dissected (frontal cortexfor 5-HT2A and striatum for D2 receptors) and examined for their contentof radioactivity. The level of non-specific binding is determined byexamining a brain region known not to contain the receptor of interest(in this case the cerebellum) or by administering an excess of compoundknown pharmacologically to interact with the receptor.

REFERENCES

Arnt, J. Acta Pharmacol. et Toxicol. 1982: 51, 321-329.

Berridge M. J., Downes P. C. , Hanley M. R. (1982) Lithium amplifiesagonist-dependent phosphotidyinositol response in brain and salivaryglands. Biochem. J., 206, 587-595.

Costall, B and Naylor, R J. Psychopharmacology. 1975: 43, 69-74.

Egan C. T., Herrick-Davis K., Miller K., Glennon R. A., and Teitler M.(1998) Agonist activity of LSD and lisuride at cloned 5-HT2A and 5-HT2Creceptors. Psychopharmacology, 136, 409-414.

Fitzgerald L W, Conklin D S, Krause C M, Marshall A P, Patterson J P,Tran D P, Iyer G, Kostich W A, Largent B L, Hartig P R (1999)High-affinity agonist binding correlates with efficacy (intrinsicactivity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidencefavoring the ternary complex and two-state models of agonist action. J.Neurochem., 72, 2127-2134.

Frost, J. J., Smith, A. C., Kuhar, M. J., Dannals, R. F., Wagner, H. N.,1987, In Vivo Binding of 3H-N-Methylspiperone to Dopamine and SerotoninReceptors. Life Sciences, 40:987-995.

Horlick, R. A., Sperle, K., Breth, L. A., Reid, C. C., Shen, E. S.,Robbinds, A. K., Cooke, G. M., Largent, B. L. (1997) Rapid Generation ofstable cell lines expressing corticotrophin-releasing hormone receptorfor drug discovery. Protein Expr. Purif. 9, 301-308.

Lucki, I, Nobler, M. S., Frazer, A., 1984, Differential actions ofserotonin antagonists on two behavioral models of serotonin receptoractivation in the rat. J. Pharmacol. Exp. Ther. 228(1):133-139.

Dosage and Formulation

The serotonin agonist and serotonin antagonist compounds of thisinvention can be administered as treatment for the control or preventionof central nervous system disorders including obesity, anxiety,depression, psychosis, schizophrenia, sleep and sexual disorders,migraine and other conditions associated with cephalic pain, socialphobias, and gastrointestinal disorders such as dysfunction of thegastrointestinal tract motility by any means that produces contact ofthe active agent with the agent's site of action, i.e., 5-HT2 receptors,in the body of a mammal. It can be administered by any conventionalmeans available for use in conjunction with pharmaceuticals, either asan individual therapeutic agent or in a combination of therapeuticagents. It can be administered alone, but preferably is administeredwith a pharmaceutical carrier selected on the basis of the chosen routeof administration and standard pharmaceutical practice.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.

The dosage administered will, of course, vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration; the age, health andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; and the effectdesired. By way of general guidance, a daily dosage of active ingredientcan be expected to be about 0.001 to about 1000 milligrams per kilogramof body weight, with the preferred dose being about 0.01 to about 100mg/kg; with the more preferred dose being about 0.1 to about 30 mg/kg.Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three, or four times daily.

Dosage forms of compositions suitable for administration contain fromabout 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions the active ingredient will ordinarily bepresent in an amount of about 0.5-95% by weight based on the totalweight of the composition. The active ingredient can be administeredorally in solid dosage forms, such as capsules, tablets and powders, orin liquid dosage forms, such as elixirs, syrups and suspensions. It canalso be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and itssalts, and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-parabenand chlorobutanol. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, supra, a standard reference text inthis field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesiumstearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil can be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 mg of the active ingredient. The capsules should then bewashed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg of starch and 98.8 mg of lactose.Appropriate coatings may be applied to increase palatability or delayabsorption.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 ml contain 25 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is sterilized bycommonly used techniques.

The Tables below provide representative Examples, the synthesis of whichare described above, of the the compounds of Formula (I) of the presentinvention.

TABLE 1

Ex # X n k R7 R8 R9 b R1 196 NHCO 1 1 H H H dbl —(CH₂)₃C(═O)(4-F-phenyl)210 NMe 2 1 H H H sgl —(CH₂)₃C(═O)(4-pryidyl) 211 NH 2 1 H H H sgl H 212NH 2 1 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl) 217 NMe 2 1 H H H sgl

218 NMe 2 1 H H H sgl

255 NMe 2 1 H H H sgl H 256 NEt 2 1 H H H sgl H 257 NPr 2 1 H H H sgl H258 N(i-Pr) 2 1 H H H sgl H 259 N(n-Bu) 2 1 H H H sgl H 260 N(CH₂Ph) 2 1H H H sgl H 261 NMe 2 1 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl) 262 NEt 2 1 HH H sgl —(CH₂)₃C(═O)(4-F-phenyl) 263 N(i-Pr) 2 1 H H H sgl—(CH₂)₃C(═O)(4-F-phenyl) 264 N(CH₂Ph) 2 1 H H H sgl—(CH₂)₃C(═O)(4-F-phenyl) 269 NMe 2 1 H H H sgl —(CH₂)₃O(4-F-phenyl) 274NMe 2 1 H 2,4-diCl-phenyl H sgl H 275 NH 2 1 H 2,4-diCl-phenyl H sgl H276 NMe 2 1 H Br H sgl —(CH₂)₃C(═O)(4-F-phenyl) 277 NMe 2 1 H MeO H sgl—(CH₂)₃C(═O)(4-F-phenyl) 278 NMe 2 1 H 2,4-diCl-phenyl H sgl H 279 NH 31 H 4-MeO-2-Me-phenyl H sgl H 280 NHCO 2 1 H 2,4-diCl-phenyl H sgl H 281NMe 2 2 H H H sgl H 282 NMe 2 2 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl) 283NHCH(Me) 1 1 H 2,4-diCl-phenyl H sgl H

TABLE 2

Ex # R7 R8 R9 b R1 4 H H F dbl —CO₂Et 5 H H F dbl H 6 H H Me dbl H 7 H HMe dbl —CO₂-tBu 8 H H Me sgl H 9 H H H sgl H 10 H H NO₂ dbl H 11 H H NO₂sgl H 12 Cl H H dbl H 13 Cl H H sgl H 14 Me H H dbl H 15 Me H H sgl H 18H H Br dbl H 19 H H Br sgl H 25 H H H sgl —C(═O)(3,4-diMeO-phenyl) 26 HH H sgl —C(═O)(2,5-diMeO-phenyl) 27 H H H sgl —C(═O)(3,5-diMeO-phenyl)28 H H H sgl 2,6-diMeO-benzyl 29 H H H sgl 2,4-diMeO-benzyl 30 H H H sgl2,4,6-triMeO-benzyl 31 H H H sgl 2,3-diMeO-benzyl 32 H H H sgl2,4,5-triMeO-benzyl 33 H H H sgl cyclohexylmethyl 34 H H H sgl2,3,4-triMeO-benzyl 35 H H H sgl 3,4-diMeO-benzyl 36 H H H sgl3,4,5-triMeO-benzyl 39 H H H sgl —CO₂Et 40 H —C(═O)CH₃ H sgl —CO₂Et 41 H—NHC(═O)CH₃ H sgl —CO₂Et 42 H H H sgl —CH₂CH₂(4-F-phenyl) 43 H H H sglEt 44 H H H sgl Pr 45 H H H sgl butyl 46 H H H sgl pentyl 47 H H H sglhexyl 48 H H H sgl 2-propyl 49 H H H sgl 2-butyl 50 H H H sgl 2-pentyl51 H H H sgl 2-hexyl 52 H H H sgl 2-Me-propyl 53 H H H sgl 2-Me-butyl 54H H H sgl 2-Me-pentyl 55 H H H sgl 2-Et-butyl 56 H H H sgl 3-Me-pentyl57 H H H sgl 3-Me-butyl 58 H H H sgl 4-Me-pentyl 59 H H H sglcyclopropylmethyl 60 H H H sgl cyclobutylmethyl 61 H H H sglcyclohexylmethyl 62 H H H sgl 2-propenyl 63 H H H sgl 2-Me-2-propenyl 64H H H sgl trans-2-butenyl 65 H H H sgl 3-Me-butenyl 66 H H H sgl3-butenyl 67 H H H sgl trans-2-pentenyl 68 H H H sgl cis-2-pentenyl 69 HH H sgl 4-pentenyl 70 H H H sgl 4-Me-3-pentenyl 71 H H H sgl3,3-diCl-2-propenyl 72 H H H sgl benzyl 73 H H H sgl 2-Me-benzyl 74 H HH sgl 3-Me-benzyl 75 H H H sgl 4-Me-benzyl 76 H H H sgl 2,5-diMe-benzyl77 H H H sgl 2,4-diMe-benzyl 78 H H H sgl 3,5-diMe-benzyl 79 H H H sgl2,4,6-triMe-benzyl 80 H H H sgl 3-MeO-benzyl 81 H H H sgl3,5-diMeO-benzyl 82 H H H sgl pentafluorobenzyl 83 H H H sgl2-phenylethyl 84 H H H sgl 1-phenyl-2-propyl 85 H H H sgltrans-3-phenyl-2-propenyl 86 H H H sgl 4-phenylbutyl 87 H H H sgl4-phenylbenzyl 88 H H H sgl 2-phenylbenzyl 169 H Me H sgl H 170 H CN Hsgl H 171 H Et H sgl H 175 H H H dbl Me 176 H H H sgl Me 177 H H H sgl H178 Cl H H sgl —(CH₂)₃C(═O)(4-F-phenyl) 179 Me H H sgl—(CH₂)₃C(═O)(4-F-phenyl) 180 H H H sgl —(CH₂)₃S(3-F-phenyl) 181 H H Hsgl —(CH₂)₃CH(OH)(4-F-phenyl) 186 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl) 187H MeO H sgl —(CH₂)₃C(═O)(4-F-phenyl) 192 H H H sgl—(CH₂)₃C(═O)(4-Br-phenyl) 193 H H H sgl —(CH₂)₃SO₂(3-F-phenyl) 194 H H Hsgl —(CH₂)₃C(═O)(4-(3,4-diCl-phenyl)phenyl) 197 H H H sgl—(CH₂)₃C(═O)(4-Me-phenyl) 198 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl) 199 H HH sgl —(CH₂)₃C(═O)(4-MeO-phenyl) 200 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl)201 H H H sgl —(CH₂)₃SO₂(4-F-phenyl) 202 H H H sgl—(CH₂)₃S(═O)(4-F-phenyl) 203 H H H sgl —(CH₂)₃O(4-F-phenyl) 204 H H Hsgl —(CH₂)₃O(phenyl) 205 H H H sgl —(CH₂)₃S(4-F-phenyl) 206 H H H sgl—(CH₂)₃NH(4-F-phenyl) 207 H H H sgl —(CH₂)₃N(CH₃)(4-F-phenyl) 208 H H Hsgl —(CH₂)₃C(═O)(4-pyridyl) 209 H H H sgl —(CH₂)₃C(═O)(3-pyridyl) 214 HH H sgl

215 H H H sgl

219 H H H sgl —(CH₂)₃CO₂Et 220 H H H sgl —(CH₂)₄CO₂Et 221 H H H sgl—(CH₂)₃C(═O)N(CH₃)(OCH₃) 222 H H H sgl —(CH₂)₄C(═O)N(CH₃)(OCH₃) 223 H HH sgl —(CH₂)₃C(═O)(3-Me-4-F-phenyl) 224 H H H sgl —(CH₂)₃C(═O)(phenyl)225 H H H sgl —(CH₂)₃C(═O)(4-Cl-phenyl) 226 H H H sgl—(CH₂)₃C(═O)(3-Me-phenyl) 227 H H H sgl —(CH₂)₃C(═O)(4-tBu-phenyl) 228 HH H sgl —(CH₂)₃C(═O)(3,4-diF-phenyl) 229 H H H sgl—(CH₂)₃C(═O)(2-MeO-5-F-phenyl) 230 H H H sgl —(CH₂)₄C(═O)(phenyl) 231 HH H sgl —(CH₂)₃C(═O)(4-F-1-naphthyl) 232 H H H sgl —(CH₂)₃C(═O)(benzyl)233 H H H sgl —(CH₂)₂C(═O)NH(4-F-phenyl) 234 H H H sgl—(CH₂)₃C(═O)NH(4-F-phenyl) 235 H H H sgl —(CH₂)₃CH(OH)(4-F-phenyl) 236 HH H sgl —(CH₂)₃CH(OH)(4-pyridyl) 237 H H H sgl—(CH₂)₃CH(OH)(2,3-diMeO-phenyl) 238 H H H sgl—(CH₂)₃C(═O)(2,3-diMeO-phenyl) 239 H H H sgl —(CH₂)₄(cyclohexyl) 240 H HH sgl —(CH₂)₃CH(phenyl)₂ 241 H H H sgl —CH₂CH₂CH═C(phenyl)₂ 242 H H Hsgl —(CH₂)₃CH(4-F-phenyl)₂ 243 H H H sgl —CH₂CH₂CH═C(4-F-phenyl)₂ 244 HH H sgl —(CH₂)₂NHC(═O)(phenyl) 245 H H H sgl —(CH₂)₂NHC(═O)(2-F-phenyl)246 H H H sgl —(CH₂)₂NHC(═O)(4-F-phenyl) 247 H H H sgl—(CH₂)₃(3-indolyl) 248 H H H sgl —(CH₂)₃(1-Me-3-indolyl) 249 H H H sgl—CH₂CH₂(3-indolyl) 250 H H H sgl —(CH₂)₃(1-indolyl) 251 H H H sgl—(CH₂)₃(1-indolinyl) 252 H H H sgl —(CH₂)₃(1-benzimidazolyl) 253 H H Hsgl

254 H H H sgl

268 H F H sgl —(CH₂)₃C(═O)(4-F-phenyl) 271 H H H sgl H 273 H F H sgl HS274 Br H H sgl H S275 2,6-diF-phenyl H H sgl H S276 2-Me-4-MeO-phenyl HH sgl H S277 4-CF₃-phenyl H H sgl H S278 2,3-diCl-phenyl H H sgl H S2792,4-diCl-phenyl H H sgl H S280 2-Cl-4-CF₃-phenyl H H sgl H S281 CN H Hsgl H S282 CN Br H sgl H S283 benzyl H H sgl H 284 CHO H H sgl H 285CO₂H H H sgl H 286 H H H sgl —(CH₂)₂NHC(═O)(2,4-diF-phenyl) 287 H H Hsgl —(CH₂)₂NMeC(═O)-phenyl 288 H H H sgl —(CH₂)₂NMeC(═O)(2-F-phenyl) 289H H H sgl —(CH₂)₂NMeC(═O)(2,4-diF-phenyl) 290 H H H sgl—(CH₂)₂NMeC(═O)(4-F-phenyl) 291 H H H sgl—(CH₂)₃(1H-1,2,3-benzotriazol-1-yl) 292 H H H sgl—(CH₂)₃(1H-1,2,3-benzotriazol-2-yl) 293 H H H sgl

294 H H H sgl

295 H H H sgl

296 H H H sgl —(CH₂)₂(1H-1,2,3-benzotriazol-1-yl) 297 H H H sgl

298 H H H sgl —(CH₂)₂(1H-1,2,3-benzotriazol-1-yl) 299 H H H sgl—(CH₂)₃(3,4-dihydro-1(2H)-quinolinyl) 300 H H H sgl—CH₂CH₂CH═CMe-(4-F-phenyl) 301 H H H sgl—(CH₂)₂(2,3-dihydro-1H-inden-2-yl) 302 H H H sgl—(CH₂)₃C(═O)(2-NH₂-phenyl) 303 H H H sgl —(CH₂)₃C(═O)(2-NH₂-phenyl) 304H H H sgl —(CH₂)₃C(═O)(2-NH₂-5-F-phenyl) 305 H H H sgl—(CH₂)₃C(═O)(2-NH₂-3-F-phenyl) 306 H H H sgl—(CH₂)₃C(═O)(2-NH₂-4-Cl-phenyl) 307 H H H sgl—(CH₂)₃C(═O)(2-NH₂-4-OH-phenyl) 308 H H H sgl—(CH₂)₃C(═O)(2-NH₂-4-Br-phenyl) 309 H H H sgl —(CH₂)₃(1H-indazol-3-yl)310 H H H sgl —(CH₂)₃(5-F-1H-indazol-3-yl) 311 H H H sgl—(CH₂)₃(7-F-1H-indazol-3-yl) 312 H H H sgl —(CH₂)₃(6-Cl-1H-indazol-3-yl)313 H H H sgl —(CH₂)₃(6-Br-1H-indazol-3-yl) 314 H H H sgl—(CH₂)₃C(═O)(2-NHMe-phenyl) 315 H H H sgl —(CH₂)₃(1-benzothien-3-yl) 355H H H sgl

356 H H H sgl —(CH₂)₃(6-F-1H-indol-1-yl) 357 H H H sgl—(CH₂)₃(5-F-1H-indol-1-yl) 358 H H H sgl—(CH₂)₃(6-F-2,3-dihydro-1H-indol-1-yl) 359 H H H sgl—(CH₂)₃(5-F-2,3-dihydro-1H-indol-1-yl) 360 H H H sgl—(CH₂)₃(6-F-1H-indol-3-yl) 361 H H H sgl —(CH₂)₃(6-F-1H-indol-3-yl) 362H H H sgl —(CH₂)₃(5-F-1H-indol-3-yl) 363 H H H sgl—(CH₂)₃(5-F-1H-indol-3-yl) 364 H H H sgl —(CH₂)₃(9H-purin-9-yl) 365 H HH sgl —(CH₂)₃(7H-purin-7-yl) 366 H H H sgl

367 H H H sgl —(CH₂)₃(6-F-1H-indazol-3-yl) 368 H H H sgl—(CH₂)₃(6-F-1H-indazol-3-yl) 369 H H H sgl —(CH₂)₃(6-F-1H-indazol-3-yl)370 H H H sgl —(CH₂)₃C(═O)(2-NH₂-4-F-phenyl) 371 H H H sgl—(CH₂)₃C(═O)(2-NH₂-4-F-phenyl) 372 H H H sgl—(CH₂)₃C(═O)(2-NHSO₂Me-4-F-phenyl) 373 H H H sgl—(CH₂)₃C(═O)(2-NHC(═O)Me-4-F-phenyl) 374 H H H sgl—(CH₂)₃C(═O)(2-NHC(═O)Me-4-F-phenyl) 375 H H H sgl—(CH₂)₃C(═O)(2-NHCO₂Et-4-F-phenyl) 376 H H H sgl—(CH₂)₃C(═O)(2-NHC(═O)NHEt-4-F-phenyl) 377 H H H sgl—(CH₂)₃C(═O)(2-NHCHO)-4-F-phenyl) 378 H H H sgl—(CH₂)₃C(═O)(2-OH-4-F-phenyl) 379 H H H sgl—(CH₂)₃C(═O)(2-MeS-4-F-phenyl) 442 H H H sgl—(CH₂)₃C(═O)(2-NHSO₂Me-4-F-phenyl) 485 H H H sgl —(CH₂)₂C(Me)CO₂Me 486 HH H sgl —(CH₂)₂C(Me)C(═O)(4-F-phenyl)₂ 487 H H H sgl—(CH₂)₂C(Me)C(OH)(4-Cl-phenyl)₂ 489 H H H sgl—(CH₂)₂C(Me)C(═O)(4-F-phenyl) 490 H H H sgl—(CH₂)₂C(Me)C(═O)(2-MeO-4-F-phenyl) 491 H H H sgl—(CH₂)₂C(Me)C(═O)(3-Me-4-F-phenyl) 492 H H H sgl—(CH₂)₂C(Me)C(═O)(2-Me-phenyl) 493 H H H sgl —(CH₂)₂C(Me)C(═O)phenyl 591Cl H H sgl —(CH₂)₃C(═O)(2-NH₂-4-F-phenyl

TABLE 2A

Ex# R7 R8 R9 b R1 115 H H Br dbl —CO₂-tBu 116 H H 2,3-diCl-phenyl dbl—CO₂-tBu 117 H H 3,4-diCl-phenyl dbl —CO₂-tBu 118 H H 2-Cl-4-CF₃-phenyldbl —CO₂-tBu 119 H H 2,3-diCl-phenyl dbl H 120 H H 3,4-diCl-phenyl dbl H121 H H 2-Cl-4-CF₃-phenyl dbl H 122 H H 2,3-diCl-phenyl sgl H 123 H H3,4-diCl-phenyl sgl H 124 H H 2-Cl-4-CF₃-phenyl sgl H 125 H H Br sgl—CO₂-tBu 126 H H 2,6-diF-phenyl sgl —CO₂-tBu 127 H H 2,6-diF-phenyl sglH 128 H 2,4-diCl-phenyl H sgl H 129 H phenyl H sgl H 130 H 4-F-phenyl Hsgl H 131 H 4-Cl-phenyl H sgl H 132 H 2-Cl-phenyl H sgl H 133 H2-MeO-phenyl H sgl H 134 H 2-Cl-4-CF₃-phenyl H sgl H 135 H2,4-diMe-phenyl H sgl H 136 H 2-Cl-4-MeO-phenyl H sgl H 137 H4-iPr-phenyl H sgl H 138 H 4-Bu-phenyl H sgl H 139 H 2-Me-4-MeO-5-F- Hsgl H phenyl 140 H 2-Me-4-MeO-phenyl H sgl H 141 H 2-Cl-4-CF₃O-phenyl Hsgl H 142 H 2,4,5-triMe-phenyl H sgl H 143 H 3-Cl-phenyl H sgl H 144 H4-Me-phenyl H sgl H 145 H 2-Me-4-Cl-phenyl H sgl H 146 H 2,5-diCl-phenylH sgl H 147 H 2-MeO-4-iPr-phenyl H sgl H 148 H 2,6-diCl-phenyl H sgl H149 H 2,6-diF-phenyl H sgl H 150 H 2-CF₃—4-MeO-phenyl H sgl H 151 H2-CF₃-phenyl H sgl H 152 H 4-pyridyl H sgl H 153 H 2-furanyl H sgl H 154H 2-thiophenyl H sgl H 155 H 4-F-phenyl H sgl H 156 H 2,3-diCl-phenyl Hsgl H 157 H 4-Et-phenyl H sgl H 158 H 2,4-diMeO-phenyl H sgl H 159 H2-F-3-Cl-phenyl H sgl H 160 H 4-MeO-phenyl H sgl H 161 H 4-MeS-phenyl Hsgl H 162 H 4-CN-phenyl H sgl H 163 H 3-CF₃-phenyl H sgl H 164 H2-MeO-phenyl H sgl H 165 H 2-naphthyl H sgl H 166 H 4-acetylphenyl H sglH 167 H 3-acetamidophenyl H sgl H 168 H 2,4-diCl-phenyl H sgl Me 316 H2,3-diMe-phenyl H sgl H 317 H 2-Me-5-F-phenyl H sgl H 318 H2-F-5-Me-phenyl H sgl H 319 H 2-MeO-5-F-phenyl H sgl H 320 H2-Me-3-Cl-phenyl H sgl H 321 H 3-NO₂-phenyl H sgl H 322 H 2-NO₂-phenyl Hsgl H 323 H 2-Cl-3-Me-phenyl H sgl H 324 H 2-MeO-phenyl H sgl H 325 H2,3-diCl-phenyl H sgl H 326 H 2-Cl-4-CF₃-phenyl H sgl H 327 H2-Me-4-EtO-phenyl H sgl H 328 H 2-Me-4-F-phenyl H sgl H 329 H4-Bu-phenyl H sgl H 330 H 2-CF₃-phenyl H sgl H 331 H 2-Cl-6-F-phenyl Hsgl H 332 H 2-Cl-4-(CHF₂)O- H sgl H phenyl 333 H 4-CF₃-phenyl H sgl H334 H 4-Me-phenyl H sgl H 335 H 4-CF₃O-phenyl H sgl H 336 H2,4-diMeO-6-F- H sgl H phenyl 337 H 2-Me-phenyl H sgl H 338 H2-CF₃-6-F-phenyl H sgl H 339 H 2-MeS-phenyl H sgl H 340 H2,4,6-triF-phenyl H sgl H 341 H 2,4,6-triCl-phenyl H sgl H 342 H2,6-diCl-4-MeO- H sgl H phenyl 343 H 2,3,4-triF-phenyl H sgl H 344 H2,6-diF-4-Cl- H sgl H phenyl 345 H 2,3,4,6-tetraF- H sgl H phenyl 346 H2,3,4,5,6-pentaF- H sgl H phenyl 347 H 2,6-diCF₃-phenyl H sgl H 348 H2-CF₃O-phenyl H sgl H 349 H 2-CF₃-4-EtO-phenyl H sgl H 350 H2-CF₃-4-iPrO- H sgl H phenyl 351 H 2-naphtyl H sgl H 352 H2-CF₃-4-Cl-phenyl H sgl H 353 H 2-CF₃-4-F-phenyl H sgl H 354 H2,4-diF-phenyl H sgl Me 380 H 2-Cl-4-EtO-phenyl H sgl H 381 H2-Cl-4-iPrO-phenyl H sgl H 382 H 2-Et-4-MeO-phenyl H sgl H 383 H2-CHO-4-MeO-phenyl H sgl H 384 H 2-CH(OH)Me-4-MeO- H sgl H phenyl 385 H2-CH(OMe)Me-4-MeO- H sgl H phenyl 386 H 2-C(═O)Me-4-MeO- H sgl H phenyl387 H 2-CH₂(OH)-4-MeO- H sgl H phenyl 388 H 2-CH₂(OMe)-4-MeO- H sgl Hphenyl 389 H 2-CH(OH)Et-4-MeO- H sgl H phenyl 390 H 2-C(═O)Et-4-MeO- Hsgl H phenyl 391 H (Z)-2-CH═CHCO₂Me-4- H sgl H MeO-phenyl 392 H2-CH₂CH₂CO₂Me-4- H sgl H MeO-phenyl 393 H (Z)-2-CH═CHCH₂(OH)- H sgl H4-MeO-phenyl 394 H (E)-2-CH═CHCO₂Me-4- H sgl H MeO-phenyl 395 H(E)-2-CH═CHCH₂(OH)- H sgl H 4-MeO-phenyl 396 H 2-CH₂CH₂OMe-4-MeO- H sglH phenyl 397 H 2-F-4-MeO-phenyl H sgl H 403 H 2-Cl-4-F-phenyl H sgl H405 H (2-Cl-phenyl)- H sgl H CH═CH— 406 H (3-Cl-phenyl)- H sgl H CH═CH—407 H (2,6-diF-phenyl)- H sgl H CH═CH— 410 H cyclohexyl H sgl H 411 Hcyclopentyl H sgl H 412 H cyclohexylmethyl H sgl H 413 H —CH₂CH₂CO₂Et Hsgl H 414 H —(CH₂)₃CO₂Et H sgl H 415 H —(CH₂)₄CO₂Et H sgl H 416 H—CH₂CH═CH₂ H sgl H 417 H Pr H sgl H 418 H benzyl H sgl H 419 H2-F-benzyl H sgl H 420 H 3-F-benzyl H sgl H 421 H 4-F-benzyl H sgl H 422H 3-MeO-benzyl H sgl H 423 H 3-OH-benzyl H sgl H 424 H 2-MeO-benzyl Hsgl H 425 H 2-OH-benzyl H sgl H 426 H 2-CO₂Me-3-MeO- H sgl H phenyl 427H 2,6-diF-phenyl H sgl H 428 H phenyl-CH═CH— H sgl H 429 H (2-Me-4-MeO-H sgl H phenyl)—CH═CH═ 430 H —NMe₂ H sgl H 431 H 1-pyrrolidinyl H sgl H432 H —NTs₂ H sgl H 433 H MeO H sgl H 445 H 2-Me-4-MeO-phenyl Me sgl H446 H 2-CF₃-4-MeO-phenyl Me sgl H 458 Me 2-CF₃-4-MeO-phenyl H sgl H 459Me 2,4-diCl-phenyl H sgl H 460 H 3-CN-phenyl H sgl H 461 H2-Me-4-CN-phenyl H sgl H 462 H 2-Me-3-CN-phenyl H sgl H 463 H2-CN-phenyl H sgl H 464 H 2-CF₃-4-CN-phenyl Me sgl H 465 H 3-CHO-phenylMe sgl H 466 H 3-CH₂(OH)-phenyl Me sgl H 467 H 3-CH₂(OMe)-phenyl Me sglH 468 H 3-CH₂(NMe₂)-phenyl Me sgl H 469 H 3-CN-4-F-phenyl Me sgl H 470 H3-CONH₂-4-F-phenyl Me sgl H 580 NH₂ H H sgl H 581 H phenyl-NH— H sgl H582 phenyl-NH— H H sgl H 583 H (4-F-phenyl)—NH— H sgl H 584 H(2,4-diCl-phenyl)—NH— H sgl H 585 H phenyl-C(═O)NH— H sgl H 586 Hbenzyl-NH— H sgl H 587 H phenyl-S— H sgl H 588 MeO H H sgl H 589 H2-CH₂(NH₂)-4-MeO- H sgl H phenyl- 590 H 2-Me-4-MeO-phenyl- H sgl H 592 H(2-Me-4-MeO-phenyl)— H sgl H NH— 593 H (2-F-4-MeO-phenyl)— H sgl H NH—595 H (2-Me-4-F-phenyl)—NH— H sgl H

TABLE 3

Ex# n k m R7 R8 R9 b R1 471 2 2 1 H H H sgl H 472 2 2 1 H H H sgl—(CH₂)₃C(═O)(4-F-phenyl) 473 2 2 1 H H H sgl —(CH₂)₃O(4-F-phenyl) 474 22 1 H H H sgl —(CH₂)₃(6-F-benzisoxazol- 3-yl) 475 2 2 1 H H H sgl—(CH₂)₃C(═O)(4-pyridyl) 476 2 3 0 H H H sgl H 477 2 3 0 H H H sgl—(CH₂)₃C(═O)(4-F-phenyl) 478 2 3 0 H H H sgl—(CH₂)_(2(6-F-benzisoxazol-) 3-yl) 483 2 2 1 H Br H sgl—(CH₂)₃C(═O)(4-F-phenyl) 484 2 2 1 H Br H sgl —(CH₂)₃O(4-F-phenyl) 488 12 1 H Br H sgl —CO₂-tBu

TABLE 3A

Ex# n k m R7 R8 R9 b R1 479 2 2 1 H 2,4-diCl-phenyl H sgl H 480 2 2 1 H2-Cl-4-MeO-phenyl H sgl H 481 2 2 1 H 2-Me-4-MeO-phenyl H sgl H 482 2 21 H Br H sgl H 497 1 1 1 H 2-Cl-phenyl H sgl H 498 1 1 1 H 3-Cl-phenyl Hsgl H 499 1 1 1 H 3-F-phenyl H sgl H 500 1 1 1 H 4-Cl-phenyl H sgl H 5011 1 1 H 4-F-phenyl H sgl H 502 1 1 1 H 2,3-diCl-phenyl H sgl H 503 1 1 1H 2,3-diF-phenyl H sgl H 504 1 1 1 H 3,5-diCl-phenyl H sgl H 505 1 1 1 H3,5-diF-phenyl H sgl H 506 1 1 1 H 3,4-diCl-phenyl H sgl H 507 1 1 1 H3,4-diF-phenyl H sgl H 508 1 1 1 H 3-Cl-4-F-phenyl H sgl H 509 1 1 1 H2-F-4-Cl-phenyl H sgl H

TABLE 4

Ex# n k m R7 R8 R9 b R1 172 2 1 1 H H H sgl H 173 1 1 1 H2,4-diCl-phenyl H sgl H 174 1 1 1 H 2-Cl-4-MeO-phenyl H sgl H 436 1 1 1H 2-Cl-phenyl H sgl H 497 1 1 1 H 2-Cl-phenyl H sgl H 498 1 1 1 H3-Cl-phenyl H sgl H 499 1 1 1 H 3-F-phenyl H sgl H 500 1 1 1 H4-Cl-phenyl H sgl H 501 1 1 1 H 4-F-phenyl H sgl H 502 1 1 1 H2,3-diCl-phenyl H sgl H 503 1 1 1 H 2,3-diF-phenyl H sgl H 504 1 1 1 H3,5-diCl-phenyl H sgl H 505 1 1 1 H 3,5-diF-phenyl H sgl H 506 1 1 1 H3,4-diCl-phenyl H sgl H 507 1 1 1 H 3,4-diF-phenyl H sgl H 508 1 1 1 H3-Cl-4-F-phenyl H sgl H 509 1 1 1 H 2-F-4-Cl-phenyl H sgl H 510 1 1 1 H2-Cl-4-F-phenyl H sgl H 511 1 1 1 H 2,5-diCl-phenyl H sgl H 512 1 1 1 H2,6-diCl-phenyl H sgl H 513 1 1 1 H 2-CF₃-phenyl H sgl H 514 1 1 1 H4-CF₃-phenyl H sgl H 515 1 1 1 H 2,4-diCF₃-phenyl H sgl H 516 1 1 1 H2-Cl-4-CF₃-phenyl H sgl H 517 1 1 1 H 2-MeO-phenyl H sgl H 518 1 1 i H2,4-diMeO-phenyl H sgl H 519 1 1 1 H 2-MeO-5-iPr-phenyl H sgl H 520 1 11 H 3-NO₂-phenyl H sgl H 521 1 1 1 H 2-CHO-phenyl H sgl H 522 1 1 1 H2-CH(Me)(OH)- H sgl H phenyl 523 1 1 1 H 2-CH_(2(OH)-phenyl) H sgl H 5241 1 1 H 2-CHO-4-MeO-phenyl H sgl H 525 1 1 1 H 2-OH-phenyl H sgl H 526 11 1 H 2-CF₃-4-EtO-phenyl H sgl H 527 1 1 1 H 2-CF₃-4-iPrO- H sgl Hphenyl 532 1 1 1 H 2-Me-4-MeO-phenyl H sgl H 533 1 1 1 H2-CF₃-4-MeO-phenyl H sgl H 534 1 2 1 H 3,4,5-triMeO- H sgl H phenyl 5351 2 1 H 1-naphthyl H sgl H 536 1 2 1 H 3-MeO-phenyl H sgl H 537 1 2 1 H2,4-diCl-phenyl H sgl H 538 1 1 2 H H H sgl H 541 2 1 1 H H H dbl H 5422 1 1 H H H sgl H 543 2 1 1 H 2,6-diF-phenyl H sgl H 545 1 2 1 H H H sglH 547 2 1 1 H 2-CF₃-4-MeO-phenyl H sgl H 548 2 1 1 H 2-Me-4-MeO-phenyl Hsgl H 549 2 1 1 H 2-Cl-4-CF₃-phenyl H sgl H 550 2 1 1 H 2,3-diCl-phenylH sgl H 551 2 1 1 H 2,4-diMeO-phenyl H sgl H 552 2 1 1 H3,4-diMeO-phenyl H sgl H 553 2 1 1 H 2,4-diCl-phenyl H sgl H 554 2 1 1 H3,4-diCl-phenyl H sgl H 555 2 1 1 H 2,5-diCl-phenyl H sgl H 556 2 1 1 H2-CF₃-phenyl H sgl H 557 2 1 1 H 2-Me-phenyl H sgl H 558 2 1 1 H2-Cl-phenyl H sgl H 559 2 1 1 H 3-F-phenyl H sgl H 560 2 1 1 H phenyl Hsgl H 561 2 1 1 H 2-CF₃-4-EtO-phenyl H sgl H 562 2 1 1 H 2-CF₃-4-iPrO- Hsgl H phenyl 563 2 1 1 H 2-MeO-4-iPr-phenyl H sgl H 564 2 1 1 H2-F-4-Cl-phenyl H sgl H 565 2 1 1 H 2-Cl-4-MeO-phenyl H sgl H 566 2 1 1H 2-CHO-phenyl H sgl H 567 2 1 1 H 2-CHO-4-MeO-phenyl H sgl H 568 2 1 1H 2-CH₂(OH)-4-MeO- H sgl H phenyl 569 2 1 1 H 2-CH₂(OH)-phenyl H sgl H570 2 1 1 H 2-CF₃-4-NHMe- H sgl H phenyl 571 2 1 1 H 2-CF₃-4-NH₂-phenylH sgl H 572 2 1 1 H 2-C(═O)Me-phenyl H sgl H 573 2 1 1 H2-C(═O)Me-4-MeO- H sgl H phenyl 574 2 1 1 H 2-CH(Me)(OH)- H sgl H phenyl575 2 1 1 H 2-CH(Me)(OH)-4- H sgl H MeO-phenyl 576 2 1 1 H2-CF₃-4-OH-phenyl H sgl H 577 2 1 1 H 2-CF₃-4-O(C═O)Me- H sgl H phenyl

TABLE 4A

Ex# n k m R7 R8 R9 b R1 182 1 1 1 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl)266 1 1 1 H H Me sgl —(CH₂)₃C(═O)(4-F- phenyl) 270 1 1 1 H H H sgl—(CH₂)₃O(4-F- phenyl) 272 1 1 1 H H H sgl H 494 1 1 1 H H H sgl—(CH₂)₃C(═O)(2-NH₂- phenyl) 495 1 1 1 H H H sgl —(CH₂)₃C(═O)(2-NH₂-phenyl) 496 1 1 1 H H H sgl —(CH₂)₃(1H-indazol- 3-yl) 528 1 1 1 H H Hsgl —(CH₂)₃(6-F-1H- indazol-3-yl) 529 1 1 1 H H H sgl—(CH₂)₃C(═O)(2-NH₂- 4-F-phenyl) 530 1 1 1 H H H sgl —(CH₂)₃C(═O)(2-NH₂-4-F-phenyl) 531 1 1 1 H H H sgl —(CH₂)₃C(═O)(2-OH- 4-F-phenyl) 539 1 2 1H H H sgl —(CH₂)₃O(4-F- phenyl) 540 1 2 1 H H H sgl —(CH₂)₃(6-F-1,2-benzisoxazol-3-yl) 544 2 1 1 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl) 546 1 21 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl)

TABLE 5

Ex# R7 R8 R9 b R1 183 H H CF₃ dbl —(CH₂)₃CH(OH)(4-F-phenyl) 184 H H CF₃dbl —(CH₂)₃C(OCH₂CH₂O)(4-F-phenyl) 185 H H CF₃ sgl —(CH₂)₄(4-F-phenyl)188 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl) 195 H H CF₃ dbl—(CH₂)₃C(═O)(4-F-phenyl) 213 H CH₃ H sgl —(CH₂)₃C(═O)(4-F-phenyl) 438 HH H sgl —(CH₂)₃C(═O)(2-NH₂-phenyl) 439 H H H sgl—(CH₂)₃C(═O)(2-NH₂-phenyl) 440 H H H sgl —(CH₂)₃C(═O)(2-NH₂-4-F-phenyl)441 H H H sgl —(CH₂)₃C(═O)(2-NH₂-4-F-phenyl) 456 H H H sgl—(CH₂)₃C(═O)(4-F-phenyl) 457 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl)

TABLE 5A

Ex# R7 R8 R9 b R1 443 2,3-diCl-phenyl H H sgl H 444 2,3-diF-phenyl H Hsgl H 447 2,6-diCl-phenyl H H sgl H 452 2-Me-4-MeO-phenyl H H sgl H 4532-Cl-6-F-phenyl H H sgl H 454 2,6-diF-phenyl H H sgl H 4552,4-diCl-phenyl H H sgl H

TABLE 6

Ex# X n R7 R8 R9 b R1 398 SO₂ 2 H 2,4-diCl-phenyl H sgl H 399 SO₂ 2 H2,6-diF-phenyl H sgl H 400 SO₂ 2 H 2-Cl-phenyl H sgl H 401 SO₂ 2 H2-F-4-MeO-phenyl H sgl H 402 SO₂ 2 H 2-Me-4-MeO-phenyl H sgl H 404 SO 2H 2-Cl-4-F-phenyl H sgl H 434 SO 2 H 2,4-diCl-phenyl H sgl H 435 SO 2 H2-Me-4-MeO-phenyl H sgl H 448 SO₂ 1 H H H sgl H 449 SO 1 H H H sgl H 450SO₂ 1 H 2-CF₃-4-MeO-phenyl H sgl H 451 SO₂ 1 H 2,4-diCl-phenyl H sgl H

TABLE 7

Ex# n R7 R8 R9 b R1 1 1 H H H dbl H 2 1 H H H dbl cycPropyl 3 1 H H Hsgl H 16 2 H H H dbl H 17 2 H H H sgl H 37 1 H H H sgl —C(═O)cycPropyl38 1 H H H sgl —C(═O)iPropyl 89 1 H 2-Cl-phenyl H sgl —CO₂-tButyl 90 1 H2,4-diCl-phenyl H sgl —CO₂-tButyl 91 1 H 3,4-diCl-phenyl H sgl—CO₂-tButyl 92 1 H 2,3-diCl-phenyl H sgl —CO₂-tButyl 93 1 H2-Cl-4-CF₃-phenyl H sgl —CO₂-tButyl 94 1 H 2-Cl-4-MeO-phenyl H sgl—CO₂-tButyl 95 1 H 2-MeO-4-iPr-phenyl H sgl —CO₂-tButyl 96 1 H3-F-phenyl H sgl —CO₂-tButyl 97 1 H 2,4-diMeO-phenyl H sgl —CO₂-tButyl98 1 H 2-Cl-phenyl H sgl H 99 1 H 2,4-diCl-phenyl H sgl H 100 1 H3,4-diCl-phenyl H sgl H 101 1 H 2,3-diCl-phenyl H sgl H 102 1 H2-Cl-4-CF₃-phenyl H sgl H 103 1 H 2-Cl-4-MeO-phenyl H sgl H 104 1 H2-MeO-4-iPr-phenyl H sgl H 105 1 H 3-F-phenyl H sgl H 106 1 H2,4-diMeO-phenyl H sgl H 107 2 H H H sgl —CO₂-tButyl 108 2 H Br H sgl—CO₂-tButyl 109 2 H 2,3-diCl-phenyl H sgl —CO₂-tButyl 110 2 H3,4-diCl-phenyl H sgl —CO₂-tButyl 111 2 H 2-Cl-4-CF₃-phenyl H sgl—CO₂-tButyl 112 2 H 2,3-diCl-phenyl H sgl H 113 2 H 3,4-diCl-phenyl Hsgl H 114 2 H 2-Cl-4-CF₃-phenyl H sgl H 189 1 H 2-Cl-phenyl H sgl—(CH₂)₃C(═O)(4-F- phenyl) 190 1 H 2,4-diCl-phenyl H sgl—(CH₂)₃C(═O)(4-F- phenyl) 191 2 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl) 2651 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl) C274 1 H 2-F-4-MeO-phenyl H sgl HC275 1 H 2-CF₃-4-EtO-phenyl H sgl —CO₂-tButyl C276 1 H2-CF₃-4-EtO-phenyl H sgl H C277 1 H 2-F-4-Cl-phenyl H sgl —CO₂-tButylC278 1 H 2-F-4-Cl-phenyl H sgl H C279 1 H 2-CF₃-4-iPrO-phenyl H sgl—CO₂-tButyl C280 1 H 2-CF₃-4-iPrO-phenyl H sgl H C281 1 H2-CF₃-4-MeO-phenyl H sgl —CO₂-tButyl C282 1 H 2-CF₃-4-MeO-phenyl H sgl HC283 1 H phenyl H sgl —CO₂-tButyl 284 1 H phenyl H sgl H 285 1 H2-Me-phenyl H sgl —CO₂-tButyl 286 1 H 2-Me-phenyl H sgl H 287 1 H2-CF₃-phenyl H sgl —CO₂-tButyl 288 1 H 2-CF₃-phenyl H sgl H 289 1 H3,4-diMeO-phenyl H sgl —CO₂-tButyl 290 1 H 3,4-diMeO-phenyl H sgl H 2911 H 2,5-diCl-phenyl H sgl —CO₂-tButyl 292 1 H 2,5-diCl-phenyl H sgl H293 1 H 3,5-diCl-phenyl H sgl —CO₂-tButyl 294 1 H 3,5-diCl-phenyl H sglH 295 1 H 2-iPr-4-MeO-phenyl H sgl —CO₂-tButyl 296 1 H2-iPr-4-MeO-phenyl H sgl H 297 1 H 2-Me-4-MeO-5-F- H sgl —CO₂-tButylphenyl 298 1 H 2-Me-4-MeO-5-F- H sgl H phenyl 299 1 H 2-Me-4-MeO-phenylH sgl —CO₂-tButyl 300 1 H 2-Me-4-MeO-phenyl H sgl H 301 1 H2-Cl-4-MeO-phenyl H sgl —CO₂-tButyl 302 1 H 2-Cl-4-MeO-phenyl H sgl H303 1 H 2-Me-4-Cl-phenyl H sgl —CO₂-tButyl 304 1 H 2-Me-4-Cl-phenyl Hsgl H 305 1 H 2-CHO-4-MeO-phenyl H sgl H 306 1 H 2,6-diCl-phenyl H sgl H307 1 H 2-CF₃-4-MeNH-phenyl H sgl H 308 1 H 2-CF₃-4-NH₂-phenyl H sgl H309 1 H 2-CH₃CH(OH)-4-MeO- H sgl H phenyl 310 3 H H H sgl H 311 3 H H Hsgl —CO₂-tButyl 312 3 H H H sgl H 313 3 H H H sgl H 314 3 H Br H sgl—CO₂-tButyl 315 3 H 2,4-diCl-phenyl H sgl H 316 3 H 2,3-diCl-phenyl Hsgl H 317 3 H 3,4-diCl-phenyl H sgl H 318 3 H 3,5-diCl-phenyl H sgl H319 3 H 2,5-diCl-phenyl H sgl H 320 3 H 2,6-diCl-phenyl H sgl H 321 3 H2-Cl-phenyl H sgl H 322 3 H 3-Cl-phenyl H sgl H 323 3 H 4-Cl-phenyl Hsgl H 324 3 H 2,6-diF-phenyl H sgl H 325 3 H 2,6-diF-phenyl H sgl H 3263 H 2,3-diF-phenyl H sgl H 327 3 H 3,4-diF-phenyl H sgl H 328 3 H3-F-phenyl H sgl H 329 3 H 2-Cl-4-CF₃-phenyl H sgl H 330 3 H2-Cl-4-MeO-phenyl H sgl H 331 3 H 2-F-4-MeO-phenyl H sgl H 332 3 H2-Me-4-MeO-phenyl H sgl H 333 3 H 2-CF₃-4-MeO-phenyl H sgl H 334 3 H2-CF₃-phenyl H sgl H 335 3 H 2-CF₃-4-iPrO-phenyl H sgl H 336 3 H2,4-diCF₃-phenyl H sgl H 337 3 H 2-CF₃-4-F-phenyl H sgl H 338 3 H2-CF₃-4-NH₂-phenyl H sgl H 339 3 H 2-CF₃-4-MeNH-phenyl H sgl H 340 3 H2-CHO-phenyl H sgl H 341 3 H 2-CH₂(OH)-phenyl H sgl H 342 3 H2-CHO-4-MeO-phenyl H sgl H 343 3 H 2-CH₂(OH)-4-MeO- H sgl H phenyl 344 3H 2-Me-4-CN-phenyl H sgl H 345 3 H 2-CH₃CH(OH)-4-MeO- H sgl H phenyl 3462 H Br H sgl —CO₂-tButyl 347 2 H 2,4-diCl-phenyl H sgl H 348 2 H3,4-diCl-phenyl H sgl H 349 2 H 3,5-diCl-phenyl H sgl H 350 2 H2,5-diCl-phenyl H sgl H 351 2 H 2,6-diCl-phenyl H sgl H 352 2 H2-Cl-phenyl H sgl H 353 2 H 3-Cl-phenyl H sgl H 354 2 H 4-Cl-phenyl Hsgl H 355 2 H 2,6-diF-phenyl H sgl H 356 2 H 2,6-diF-phenyl H sgl Me 3572 H 2,3-diF-phenyl H sgl H 358 2 H 3,4-diF-phenyl H sgl H 359 2 H3-F-phenyl H sgl H 360 2 H 2-Cl-4-MeO-phenyl H sgl H 361 2 H2-F-4-MeO-phenyl H sgl H 362 2 H 2-Me-4-MeO-phenyl H sgl H 363 2 H2-CF₃-4-MeO-phenyl H sgl H 364 2 H 2-CF₃-4-MeO-phenyl H dbl H 365 2 H2-CF₃-4-OH-phenyl H sgl H 366 2 H 2-CF₃-phenyl H sgl H 367 2 H2-CF₃-4-iPrO-phenyl H sgl H 368 2 H 2,4-diCF₃-phenyl H sgl H 369 2 H2-CF₃-4-F-phenyl H sgl H 370 2 H 2-CF₃-4-NH₂-phenyl H sgl H 371 2 H2-CF₃-4-MeNH-phenyl H sgl H 372 2 H 4-CN-2-Me-phenyl H sgl H 373 2 H2-CHO-phenyl H sgl H 374 2 H 2-CH₂(OH)-phenyl H sgl H 375 2 H2-CHO-4-MeO-phenyl H sgl H 376 2 H 2-CH₂(OH)-4-MeO- H sgl H phenyl 377 3H 2-CF₃-4-EtO-phenyl H sgl H 378 2 H 2-CF₃-4-EtO-phenyl H sgl H 379 3 H2-Me-3-Cl-phenyl H sgl H 380 2 H 2-Me-3-Cl-phenyl H sgl H 381 2 H2-Me-5-F-phenyl H sgl H 382 2 H 2,3-diCl-phenyl H sgl Pr 383 2 H2,3-diCl-phenyl H sgl Pr 384 2 H 2,3-diCl-phenyl H sgl Bu 385 2 H2,3-diCl-phenyl H sgl Bu 386 2 H 2,3-diCl-phenyl H sgl 4-pentenyl 387 2H 2,3-diCl-phenyl H sgl 3-Me-2-butenyl 388 2 H 2,4-diCl-phenyl H sgl Pr389 2 H 2,4-diCl-phenyl H sgl Bu 390 2 H 2,4-diCl-phenyl H sgl4-pentenyl 391 2 H 2,4-diCl-phenyl H sgl 3-Me-2-butenyl 392 2 H2,4-diCl-phenyl H sgl cyclobutylmethyl 393 2 H 2-CF₃-4-MeO-phenyl H sglMe 394 2 H 2-CF₃-4-MeO-phenyl H sgl Et 395 2 H 2-CF₃-4-MeO-phenyl H sglPr 396 2 H 2-CF₃-4-MeO-phenyl H sgl Bu 397 2 H 2-CF₃-4-MeO-phenyl H sgl4-pentenyl 398 2 H 2-CF₃-4-MeO-phenyl H sgl 3-Me-2-butenyl 399 2 H2-CF₃-4-MeO-phenyl H sgl 2-F-ethyl 400 2 H 2-CF₃-4-MeO-phenyl H sgl2,2-diF-ethyl 401 2 H 2-CF₃-4-MeO-phenyl H sgl cyclobutylmethyl 402 2 HH H sgl —(CH₂)₃C(═O)(4-F- phenyl) 403 2 H H H sgl —(CH₂)₃C(═O)(4-F-phenyl) 403 2 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl) 404 2 H H H sgl—(CH₂)₃C(═O)(2- NH₂-phenyl) 405 2 H H H sgl —(CH₂)₃C(═O)(2- NH₂-phenyl)406 2 H H H sgl —(CH₂)₃C(4-F- phenyl) 407 2 H H H sgl —(CH₂)₃C(═O)(4-pyridyl) 408 2 H H H sgl

409 2 H H H sgl

410 2 H H H dbl —(CH₂)₃C(═O)(4-F- phenyl) 411 3 H H H sgl—(CH₂)₃C(═O)(4-F- phenyl) 412 3 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl) 4133 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl) 414 3 H H H sgl —(CH₂)₃C(═O)(2-NH₂-4-F-phenyl) 415 2 H H H sgl —(CH₂)₃C(═O)(2- NH₂-4-F-phenyl) 416 2 HH H sgl —(CH₂)₃C(═O)(2- NH₂-4-F-phenyl) 417 2 H H H sgl —(CH₂)₃C(═O)(2-NH₂-4-F-phenyl)

TABLE 8

Ex# n k m R7 R8 R9 b R1 418 2 2 1 H H H dbl H 419 2 2 1 H H H sgl H 4202 2 1 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl) 421 2 2 1 H H H sgl—(CH₂)₃C(═O)(2- NH₂-4-F-phenyl) 422 3 2 1 H H H dbl H 423 3 2 1 H H Hsgl H 424 3 2 1 H H H sgl —(CH₂)₃C(═O)(4-F- phenyl) 425 3 2 1 H H H sgl—(CH₂)₃C(═O)(2- NH₂-4-F-phenyl) 434 2 1 2 H H H sgl H 435 2 1 2 H H Hsgl —CO₂-tButyl 436 2 1 2 H Br H sgl —CO₂-tButyl 437 2 1 2 H 2-CF₃-4- Hsgl H MeO-phenyl

TABLE 9

Ex# X R7 R8 R9 b R1 426 C═O H H H sgl H 427 C═O H H H sgl —CO₂-tButyl428 C═O H 2,4-diCl-phenyl H sgl —CO₂-tButyl 429 C═O H 2,4-diCl-phenyl Hsgl H 430 C═O H 2,4-diCl-phenyl H sgl H 431 C═O H 2,4-diCl-phenyl H sglH 432 CH(OH) H 2,4-diCl-phenyl H sgl H 433 CH(OH) H 2,4-diCl-phenyl Hsgl H

What is claimed is:
 1. A compound of the formula (I)

or stereoisomers or pharmaceutically acceptable salt forms thereof,wherein: b is a single bond; X is —NR^(10A)—; R¹ is selected from H,C(═O)R², C(═O)OR², C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇cycloalkyl, C₁₋₆ alkyl substituted with Z, C₂₋₆ alkenyl substituted withZ, C₂₋₆ alkynyl substituted with Z, C₃₋₆ cycloalkyl substituted with Z,aryl substituted with Z, 5-6 membered heterocyclic ring systemcontaining at least one heteroatom selected from the group consisting ofN, O, and S, said heterocyclic ring system substituted with Z; C₁₋₃alkyl substituted with Y, C₂₋₃ alkenyl substituted with Y, C₂₋₃ alkynylsubstituted with Y, C₁₋₆ alkyl substituted with 0-2 R², C₂₋₆ alkenylsubstituted with 0-2 R², C₂₋₆ alkynyl substituted with 0-2 R², arylsubstituted with 0-2 R², and 5-6 membered heterocyclic ring systemcontaining at least one heteroatom selected from the group consisting ofN, O, and S, said heterocyclic ring system substituted with 0-2 R²; Y isselected from C₃₋₆ cycloalkyl substituted with Z, aryl substituted withZ, 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with Z; C₃₋₆ cycloalkyl substitutedwith —(C₁₋₃ alkyl)-Z, aryl substituted with —(C₁₋₃ alkyl)-Z, and 5-6membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with —(C₁₋₃ alkyl)-Z; Z is selected from H,—CH(OH)R², —C(ethylenedioxy)R², —OR², —SR², —NR²R³, —C(O)R², —C(O)NR²R³,—NR³C(O)R², —C(O)OR², —OC(O) R², —CH(═NR⁴)NR²R³, —NHC(═NR⁴)NR²R³,—S(O)R², —S(O)₂R², —S(O)₂NR²R³, and —NR³S(O)₂R²; R², at each occurrence,is independently selected from halo, C₁₋₃ haloalkyl, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, aryl substituted with 0-5 R⁴²;C₃₋₁₀ carbocyclic group substituted with 0-3 R⁴¹, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R⁴¹; R³, ateach occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ alkoxy; alternatively, R² and R³ join toform a 5- or 6-membered ring optionally substituted with —O— or —N(R⁴)—;R⁴, at each occurrence, is independently selected from H and C₁₋₄ alkyl;R⁵ is H or C₁₋₄ alkyl; R^(6a) and R^(6b), at each occurrence, areindependently selected from H, —OH, —NR⁴⁶R⁴⁷, —CF₃, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, andaryl substituted with 0-3 R⁴⁴; R⁷ and R⁹, at each occurrence, areindependently selected from H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,—NR⁴⁶R⁴⁷, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,C₁₋₄ alkyl substituted with 0-2 R¹¹, C₃₋₁₀ carbocyclic group substitutedwith 0-3 R³³, aryl substituted with 0-5 R³³, 5-10 membered heterocyclicring system containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³,C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O) NHR¹⁵; R⁸ is selected from H, halo, —CF₃,—OCF₃, —OH, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkylsubstituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2 R¹¹, C₂₋₄alkenyl substituted with 0-2 R¹¹, C₂₋₄ alkynyl substituted with 0-1 R¹¹,C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, aryl substituted with0-5 R³³, 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O) NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵; R^(10A) is selected from H, C₁₋₆ alkylsubstituted with 0-1 R^(10B), C₂₋₆ alkenyl substituted with 0-1 R^(10B),C₂₋₆ alkynyl substituted with 0-1 R¹⁰, and C₁₆ alkoxy; R^(10B) isselected from C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, phenyl substituted with 0-3 R³³, and 5-6membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴; R¹¹ is selected from H, halo, —CF₃, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl,C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, aryl substituted with0-5 R³³, 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O) NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O) NHR¹⁵; R¹², at each occurrence, isindependently selected from C₁₋₄ alkyl substituted with 0-1 R^(12a),C₂₋₄ alkenyl substituted with 0-1 R^(12a), C₂₋₄ alkynyl substituted with0-1 R^(12a), C₃₋₆ cycloalkyl substituted with 0-3 R³³, phenylsubstituted with 0-5 R³³; C₃₋₁₀ carbocyclic group substituted with 0-3R³³, and 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R^(12a), at each occurrence, is independentlyselected from phenyl substituted with 0-5 R³³; C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; R¹³, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—; alternatively, R¹² and R¹³when attached to N may be combined to form a 9- or 10-membered bicyclicheterocyclic ring system containing from 1-3 heteroatoms selected fromthe group consisting of N, O, and S, wherein said bicyclic heterocyclicring system is unsaturated or partially saturated, wherein said bicyclicheterocyclic ring system is substituted with 0-3 R¹⁶; R¹⁴, at eachoccurrence, is independently selected from H 12 and C₁₋₄ alkyl; R¹⁵, ateach occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl; R¹⁶, at each occurrence, is independentlyselected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₃ haloalkyl-oxy-,and C₁₋₃ alkyloxy-; R³¹, at each occurrence, is independently selectedfrom H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl; R³³, at eachoccurrence, is independently selected from H, OH, halo, CN, NO₂, CF₃,SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄ alkyloxy-, C₁₋₄alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-;C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; andC₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy;R⁴¹, at each occurrence, is independently selected from H, CF₃, halo,OH, —CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O; C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl C₁₋₄ alkyl substituted with 0-1 R⁴³, arylsubstituted with 0-3 R⁴², and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴⁴; R⁴², at each occurrence, isindependently selected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵,NR⁴⁶SO₂R⁴⁵, NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkyl substituted with 0-1 R⁴³, aryl substituted with 0-3 R⁴⁴, and5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴; R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴; R⁴⁴, ateach occurrence, is independently selected from H, halo, —OH, NR⁴⁶R⁴⁷,CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄ alkoxy; R⁴⁵is C₁₋₄ alkyl; R⁴⁶, at each occurrence, is independently selected from Hand C₁₋₄ alkyl; R⁴⁷, at each occurrence, is independently selected fromH, C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —SO₂ (C₁₋₄ alkyl), —C(═O)O(C₁₋₄alkyl), —C(═O) (C₁₋₄ alkyl), and —C(═O)H; k is 1 or 2; m is 0, 1, or 2;and n is 1, 2, or 3; provided when m is 0 or 1 then k is 1 or 2;provided when m is 2 then k is
 1. 2. A compound of claim 1 wherein: X is—NR^(10A)—; R¹ is selected from H, C(═O) R², C(═O)OR², C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl substituted with 0-2R², C₂₋₆ alkenyl substituted with 0-2 R², C₂₋₆ alkynyl substituted with0-2 R², aryl substituted with 0-2 R², and 5-6 membered heterocyclic ringsystem containing at least one heteroatom selected from the groupconsisting of N, O, and S, said heterocyclic ring system substitutedwith 0-2 R²; R², at each occurrence, is independently selected from F,Cl, CH₂F, CHF₂, CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, phenyl substituted with 0-5 R⁴²; C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R⁴¹, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴¹; R⁵ is H, methyl, ethyl, propyl, orbutyl; R^(6a) is selected from H, —OH, —NR⁴⁶R⁴⁷, —CF₃, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, and aryl substituted with 0-3 R⁴⁴; R^(6b) is H;R⁷ and R⁹, at each occurrence, are independently selected from H, halo,—CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀cycloalkyl substituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2R¹¹, C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, aryl substitutedwith 0-5 R³³, 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; OR¹², SR¹², NR¹²R^(13,) C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R^(1 3,) NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O) NR¹²R¹³S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S (O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O) NHR¹⁵; R⁸ is selected from H, halo, —CF₃,—OCF₃, —OH, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkylsubstituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2 R¹¹, C₂₋₄alkenyl substituted with 0-2 R¹¹, C₂₋₄ alkynyl substituted with 0-1 R¹¹,C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, aryl substituted with0-5 R³³, 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O) NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O) R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵; R^(10A) is selected from H, C₁₋₆ alkylsubstituted with 0-1 R^(10B), C₂₋₆ alkenyl substituted with 0-1 R^(10B),C₂₋₆ alkynyl substituted with 0-1 R^(10B), and C₁₋₆ alkoxy; R^(10B) isselected from C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, phenyl substituted with 0-3 R³³, and 5-6membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴; R¹¹ is selected from H, halo, —CF₃, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl,C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, aryl substituted with0-5 R³³, 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O) NHR¹⁵; R¹², at each occurrence, isindependently selected from C₁₋₄ alkyl substituted with 0-1 R^(12a),C₂₋₄ alkenyl substituted with 0-1 R^(12a), C₂₋₄ alkynyl substituted with0-1 R^(12a), C₃₋₆ cycloalkyl substituted with 0-3 R³³, phenylsubstituted with 0-5 R³³; C₃₋₁₀ carbocyclic group substituted with 0-3R³³, and 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R^(12a), at each occurrence, is independentlyselected from phenyl substituted with 0-5 R³³; C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; R¹³, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—; alternatively, R¹² and R¹³when attached to N may be combined to form a 9- or 10-membered bicyclicheterocyclic ring system containing from 1-3 heteroatoms selected fromthe group consisting of N, O, and S, wherein said bicyclic heterocyclicring system is unsaturated or partially saturated, wherein said bicyclicheterocyclic ring system is substituted with 0-3 R¹⁶; R¹⁴, at eachoccurrence, is independently selected from H and C₁₋₄ alkyl; R¹⁵, ateach occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl; R¹⁶, at each occurrence, is independentlyselected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₃ haloalkyl-oxy-,and C₁₃ alkyloxy-; R³¹, at each occurrence, is independently selectedfrom H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl; R³³, at eachoccurrence, is independently selected from H, OH, halo, CN, NO₂, CF₃,SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄ alkyloxy-, C₁₋₄alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-;C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; andC₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy;R⁴¹, at each occurrence, is independently selected from H, CF₃, halo,OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN; C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl C₁₋₄ alkyl substituted with 0-1 R⁴³, arylsubstituted with 0-3 R⁴², and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴⁴; R⁴², at each occurrence, isindependently selected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷,NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-1R⁴³, aryl substituted with 0-3 R⁴⁴, and 5-10 membered heterocyclic ringsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R⁴⁴; R⁴³ is C₃₋₆cycloalkyl or aryl substituted with 0-3 R⁴⁴; R⁴⁴, at each occurrence, isindependently selected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃,—OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄ alkoxy; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶,at each occurrence, is independently selected from H and C₁₋₄ alkyl;R⁴⁷, at each occurrence, is independently selected from H and C₁₋₄alkyl; k is 1 or 2; m is 0, 1, or 2; and n is 1, 2, or
 3. 3. A compoundof claim 2 wherein: X is —NR^(10A)—; R¹ is selected from H, C(═O)R²,C(═O)OR², C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄alkyl substituted with 0-2 R², C₂₋₄ alkenyl substituted with 0-2 R², andC₂₋₄ alkynyl substituted with 0-2 R²; R², at each occurrence, isindependently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, phenyl substituted with 0-5 R⁴²; C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R⁴¹, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴¹; R⁵ is H, methyl, ethyl, propyl, orbutyl; R^(6a) is selected independently from H, —OH, —NR⁴⁶R⁴⁷, —CF₃,C₁₋₃ alkyl, and C₁₋₃ alkoxy; R^(6b) is H; R⁷ and R⁹, at each occurrence,are independently selected from H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,—NR⁴⁶R⁴⁷, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₆ haloalkyl, C₁₋₆alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,C₁₋₄ alkyl substituted with 0-2 R¹¹, C₃₋₁₀ carbocyclic group substitutedwith 0-3 R³³, aryl substituted with 0-5 R³³, 5-10 membered heterocyclicring system containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³,C(O)H, C(O)R¹² _(,) C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹²,OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²; R⁸ is selectedfrom H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀cycloalkyl substituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2R¹¹, C₂₋₄ alkenyl substituted with 0-2 R¹¹, C₂₋₄ alkynyl substitutedwith 0-1 R¹¹, C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, arylsubstituted with 0-5 R³³, 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O) NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O) R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O) NHR¹⁵; R^(10A) is selected from H, C₁₋₄ alkylsubstituted with 0-1 R^(10B), C₂₋₄ alkenyl substituted with 0-1 R^(10B),C₂₋₄ alkynyl substituted with 0-1 R^(10B), and C₁₋₆ alkoxy; R^(10B) isselected from C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, phenyl substituted with 0-3R³³, and 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴⁴; R¹¹ is selected from H, halo, —CF₃, —CN, —NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₆ alkoxy,C₃₋₁₀ cycloalkyl, C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, arylsubstituted with 0-5 R³³, 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹ ²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O) R¹², and NR¹⁴S(O)₂R¹²; R¹², at each occurrence,is independently selected from C₁₋₄ alkyl substituted with 0-1 R^(12a),C₂₋₄ alkenyl substituted with 0-1 R^(12a), C₂₋₄ alkynyl substituted with0-1 R^(12a), C₃₋₆ cycloalkyl substituted with 0-3 R³³, phenylsubstituted with 0-5 R³³; C₃₋₁₀ carbocyclic group substituted with 0-3R³³, and 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R^(12a), at each occurrence, is independentlyselected from phenyl substituted with 0-5 R³³; C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; R¹³, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—; alternatively, R¹² and R¹³when attached to N may be combined to form a 9- or 10-membered bicyclicheterocyclic ring system containing from 1-3 heteroatoms selected fromthe group consisting of N, O, and S, wherein said bicyclic heterocyclicring system is unsaturated or partially saturated, wherein said bicyclicheterocyclic ring system is substituted with 0-3 R¹⁶; R¹⁴, at eachoccurrence, is independently selected from H, methyl, ethyl, propyl, andbutyl; R¹⁵, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R¹⁶, at each occurrence, isindependently selected from H, OH, F, Cl, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷,—C(═O)H, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, andtrifluoromethoxy; R³¹, at each occurrence, is independently selectedfrom H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl; R³³, at eachoccurrence, is independently selected from H, OH, halo, CN, NO₂, CF₃,SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄ alkyloxy-, C₁₋₄alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-;C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; andC₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy;R⁴¹, at each occurrence, is independently selected from H, CF₃, halo,OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl C₁₋₄ alkyl substituted with 0-1 R⁴³, arylsubstituted with 0-3 R⁴², and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴⁴; R⁴², at each occurrence, isindependently selected from H, CF₃, halo, OH, CO₂H, SO₂R⁴5, NR⁴⁶R⁴⁷,NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-1R⁴³, aryl substituted with 0-3 R⁴⁴, and 5-10 membered heterocyclic ringsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R⁴⁴; R⁴³ is C₃₋₆cycloalkyl or aryl substituted with 0-3 R⁴⁴; R⁴⁴, at each occurrence, isindependently selected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵,—CF3,—OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄ alkoxy; R⁴⁵ is C₁₋₄ alkyl;R⁴⁶, at each occurrence, is independently selected from H and C₁₋₄alkyl; R⁴⁷, at each occurrence, is independently selected from H andC₁₋₄ alkyl; k is 1 or 2; m is 0 or 1; and n is 1 or
 2. 4. A compound ofclaim 2 wherein: X is —NH—; R¹ is selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₄ cycloalkyl, C₁₋₃ alkyl substituted with 0-1R², C₂₋₃ alkenyl substituted with 0-1 R², and C₂₋₃ alkynyl substitutedwith 0-1 R²; R², at each occurrence, is independently selected from C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, phenyl substitutedwith 0-5 R⁴²; C₃₋₆ carbocyclic group substituted with 0-3 R⁴¹, and 5-6membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹; R⁵ is H, methyl, ethyl, propyl, or butyl; R^(6a) is H, methyl,ethyl, methoxy, —OH, or —CF₃; R^(6b) is H; R⁷ and R⁹, at eachoccurrence, are independently selected from H, halo, —CF₃, —OCF₃, —OH,—CN, —NO₂, —NR⁴⁶R⁴⁷, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkylsubstituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2 R¹¹, C₃₋₁₀carbocyclic group substituted with 0-3 R³³, aryl substituted with 0-5R³³, and 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R⁸ is selected from H, halo, —CF₃, —OCF₃, —OH,—CN, —NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,C₁₋₄ alkyl substituted with 0-2 R¹¹, C₂₋₄ alkenyl substituted with 0-2R¹¹, C₂₋₄ alkynyl substituted with 0-1 R¹¹, C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-6 memberedheterocyclic ring system containing 1, 2, or 3 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; OR¹²,SR¹², NR¹²R¹³, NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, andNR¹²C(O)NHR¹⁵; R¹¹ is selected from H, halo, —CF₃, —CN, —NO₂, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, (C₁₋₄haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³, C₃₋10carbocyclic group substituted with 0-3 R³³, aryl substituted with 0-5R³³, and 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R¹², at each occurrence, is independentlyselected from C₁₋₄ alkyl substituted with 0-1 R^(12a), C₂₋₄ alkenylsubstituted with 0-1 R^(12a), C₂₋₄ alkynyl substituted with 0-1 R^(12a),C₃₋₆ cycloalkyl substituted with 0-3 R³³, phenyl substituted with 0-5R³³; C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; R^(12a),at each occurrence, is independently selected from phenyl substitutedwith 0-5 R³³; C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, and 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹; R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; alternatively, R¹² and R¹³ jointo form a 5- or 6-membered ring optionally substituted with —O— or—N(R¹⁴)—; alternatively, R¹² and R¹³ when attached to N may be combinedto form a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of one N, two N,three N, one N one O, and one N one S; wherein said bicyclicheterocyclic ring system is unsaturated or partially saturated, whereinsaid bicyclic heterocyclic ring system is substituted with 0-2 R¹⁶; R¹⁴,at each occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; R¹⁵, at each occurrence, is independently selectedfrom H, methyl, ethyl, propyl, and butyl; R¹⁶, at each occurrence, isindependently selected from H, OH, F, Cl, CN, NO₂, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R³¹, at eachoccurrence, is independently selected from H, OH, halo, CF₃, methyl,ethyl, and propyl; R³³, at each occurrence, is independently selectedfrom H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkyl-oxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—, C₁₋₄ alkyl-C(═O)O—, C₃₋₆cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-; C₁₋₆ alkyl substituted withOH, methoxy, ethoxy, propoxy, or butoxy; and C₂₋₆ alkenyl substitutedwith OH, methoxy, ethoxy, propoxy, or butoxy; R⁴¹, at each occurrence,is independently selected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷,NO₂, CN, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, andC₁₋₃ alkyl; R⁴², at each occurrence, is independently selected from H,CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, and C₁₋₃ alkyl; R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, or pyridyl, each substituted with 0-3 R⁴⁴; R⁴⁴, ateach occurrence, is independently selected from H, halo, —OH, NR⁴⁶R⁴⁷,CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, and butoxy; R⁴⁵ is methyl, ethyl, propyl, orbutyl; R⁴⁶, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl; R⁴⁷, at each occurrence, isindependently selected from from H, methyl, ethyl, propyl, and butyl; kis 1; m is 1; and n is 1 or
 2. 5. A compound of claim 2 wherein: X is—NH—; R¹ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₄ cycloalkyl, C₁₋₃ alkyl substituted with 0-1 R², C₂₋₃ alkenylsubstituted with 0-1 R², and C₂₋₃ alkynyl substituted with 0-1 R²; R²,at each occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, phenyl substituted with 0-5 R⁴²;C₃₋₆ carbocyclic group substituted with 0-3 R⁴¹, and 5-6 memberedheterocyclic ring system containing 1, 2, or 3 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R⁴¹; R⁵ is H,methyl, ethyl, propyl, or butyl; R^(6a) is H, methyl, ethyl, methoxy,—OH, or —CF₃; R^(6b) is H; R⁷ and R⁹, at each occurrence, areindependently selected from H, F, C_(1,)-CH₃, —OCH₃, —CF₃, —OCF₃, —CN,and —NO₂, R⁸ is selected from H, F, Cl, Br, —CF₃, —OCF₃, —OH, —CN, —NO₂,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,(C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³, C₁₋₄alkyl substituted with 0-2 R¹¹, C₂₋₄ alkenyl substituted with 0-2 R¹¹,C₂₋₄ alkynyl substituted with 0-1 R¹¹, C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-6 memberedheterocyclic ring system containing 1, 2, or 3 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; OR¹²,SR¹², NR¹²R¹³, NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, andNR¹²C(O)NHR¹⁵; R¹¹ is selected from H, halo, —CF₃, —CN, —NO₂, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, (C₁₋₄haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³, C₃₋₁₀carbocyclic group substituted with 0-3 R³³, aryl substituted with 0-5R³³, and 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R¹², at each occurrence, is independentlyselected from C₁₋₄ alkyl substituted with 0-1 R^(12a), C₂₋₄ alkenylsubstituted with 0-1 R^(12a), C₂₋₄ alkynyl substituted with 0-1 R^(12a),C₃₋₆ cycloalkyl substituted with 0-3 R³³, phenyl substituted with 0-5R³³; C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; R^(12a),at each occurrence, is independently selected from phenyl substitutedwith 0-5 R³³; C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, and 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹; R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; alternatively, R¹² and R¹³ jointo form a 5- or 6-membered ring optionally substituted with —O— or—N(R¹⁴)—; alternatively, R¹² and R¹³ when attached to N may be combinedto form a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of N, O, and S;wherein said bicyclic heterocyclic ring system is selected from indolyl,indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl,benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl;wherein said bicyclic heterocyclic ring system is substituted with 0-1R¹⁶; R¹⁴, at each occurrence, is independently selected from H, methyl,ethyl, propyl, and butyl; R¹⁵, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, and butyl; R¹⁶, at eachoccurrence, is independently selected from H, OH, F, Cl, CN, NO₂,methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy;R³¹, at each occurrence, is independently selected from H, OH, halo,CF₃, methyl, ethyl, and propyl; R³³, at each occurrence, isindependently selected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷,—C(═O)H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—, C₁₋₄alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-; C₁₋₆alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and C₂₋₆alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R⁴¹,at each occurrence, is independently selected from H, CF₃, halo, OH,CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₃ alkoxy,C₁₋₃ haloalkyl, and C₁₋₃ alkyl; R⁴², at each occurrence, isindependently selected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷,NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, and C₁₋₃ alkyl; R⁴³ iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl,each substituted with 0-3 R⁴⁴; R⁴⁴, at each occurrence, is independentlyselected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN,—NO₂, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, andbutoxy; R⁴⁵ is methyl, ethyl, propyl, or butyl; R⁴⁶, at each occurrence,is independently selected from H, methyl, ethyl, propyl, and butyl; R⁴⁷,at each occurrence, is independently selected from from H, methyl,ethyl, propyl, and butyl; k is 1; m is 1; and n is 1 or
 2. 6. A compoundof claim 2 wherein: X is —NH—; R¹ is selected from H, C₁₋₅ alkylsubstituted with 0-1 R², C₂₋₅ alkenyl substituted with 0-1 R², and C₂₋₃alkynyl substituted with 0-1 R²; R² is C₃₋₆ cycloalkyl; R⁵ is H, methyl,ethyl, or propyl; R^(6a) is H, methyl, or ethyl; R^(6b) is H; R⁷ and R⁹,at each occurrence, are independently selected from H, F, Cl, —CH₃,—OCH₃, —CF₃, —OCF₃, —CN, and —NO₂, R⁸ is selected from methylsubstituted with R¹¹; ethenyl substituted with R¹¹; OR¹²e SR¹²,NR¹²R^(—)3, NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵;R¹¹ is selected from phenyl-substituted with 0-5 fluoro;2-(H₃CCH₂C(═O))-phenyl-substituted with R³³;2-(H₃CC(═O))-phenyl-substituted with R³³; 2-(HC(═O))-phenyl-substitutedwith R³³; 2-(H₃CCH(OH))-phenyl-substituted with R³³;2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;2-(HOCH₂)-phenyl-substituted with R³³; 2-(HOCH₂CH₂)-phenyl-substitutedwith R³³; 2-(H₃COCH₂)-phenyl-substituted with R³³;2-(H₃COCH₂CH₂)-phenyl-substituted with R³³;2-(H₃CCH(OMe))-phenyl-substituted with R³³;2-(H₃COC(═O))-phenyl-substituted with R³³;2-(HOCH₂CH═CH)-phenyl-substituted with R³³;2-((MeOC═O)CH═CH)-phenyl-substituted with R³³;2-(methyl)-phenyl-substituted with R^(33;) 2-(ethyl)-phenyl-substitutedwith R³³; 2-(i-propyl)-phenyl-substituted with R³³;2-(F₃C)-phenyl-substituted with R³³; 2-(NC)-phenyl-substituted with R³³;2-(H₃CO)-phenyl-substituted with R³³; 2-(fluoro)-phenyl-substituted withR³³; 2-(chloro)-phenyl-substituted with R³³; 3-(NC)-phenyl-substitutedwith R³³; 3-(H₃CO)-phenyl-substituted with R³³;3-(fluoro)-phenyl-substituted with R³³; 3-(chloro)-phenyl-substitutedwith R³³; 4-(NC)-phenyl-substituted with R³³;4-(fluoro)-phenyl-substituted with R³³; 4-(chloro)-phenyl-substitutedwith R³³; 4-(H₃CS)-phenyl-substituted with R³³;4-(H₃CO)-phenyl-substituted with R³³; 4-(ethoxy)-phenyl-substituted withR³³; 4-(i-propoxy)-phenyl-substituted with R³³;4-(i-butoxy)-phenyl-substituted with R³³;4-(H₃CCH₂CH₂C(═O))-phenyl-substituted with R³³;4-((H₃C)₂CHC(═O))-phenyl-substituted with R³³;4-(H₃CCH₂C(═O))-phenyl-substituted with R³³;4-(H₃CC(═O))-phenyl-substituted with R³³;4-(H₃CCH₂CH₂CH(OH))-phenyl-substituted with R³³; 4-((H₃C)₂CHCH(OH))-phenyl-substituted with R³³; 4-(H₃CCH₂CH(OH))-phenyl-substitutedwith R³³; 4-(H₃CCH(OH))-phenyl-substituted with R³³;4-(cyclopropyloxy)-phenyl-substituted with R³³;4-(cyclobutyloxy)-phenyl-substituted with R³³; and4-(cyclopentyloxy)-phenyl-substituted with R³³; R¹² is selected fromphenyl-substituted with 0-5 fluoro; 2-(H₃CCH₂C(═O))-phenyl-substitutedwith R³³; 2-(H₃CC(═O))-phenyl-substituted with R³³;2-(HC(═O))-phenyl-substituted with R³³; 2-(H₃CCH(OH))-phenyl-substitutedwith R³³; 2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;2-(HOCH₂)-phenyl-substituted with R³³; 2-(HOCH₂CH₂)-phenyl-substitutedwith R³³; 2-(H₃COCH₂)-phenyl-substituted with R³³;2-(H₃COCH₂CH₂)-phenyl-substituted with R³³;2-(H₃CCH(OMe))-phenyl-substituted with R³³;2-(H₃COC(═O))-phenyl-substituted with R³³;2-(HOCH₂CH═CH)-phenyl-substituted with R³³;2-((MeOC═O)CH═CH)-phenyl-substituted with R³³;2-(methyl)-phenyl-substituted with R³³; 2-(ethyl)-phenyl-substitutedwith R³³; 2-(i-propyl)-phenyl-substituted with R³³;2-(F₃C)-phenyl-substituted with R³³; 2-(NC)-phenyl-substituted with R³³;2-(H₃CO)-phenyl-substituted with R³³; 2-(fluoro)-phenyl-substituted withR³³; 2-(chloro)-phenyl-substituted with R³³; 3-(NC)-phenyl-substitutedwith R³³; 3-(H₃CO)-phenyl-substituted with R³³;3-(fluoro)-phenyl-substituted with R³³; 3-(chloro)-phenyl-substitutedwith R³³; 4-(NC)-phenyl-substituted with R³³;4-(fluoro)-phenyl-substituted with R³³; 4-(chloro)-phenyl-substitutedwith R³³; 4-(H₃CS)-phenyl-substituted with R³³;4-(H₃CO)-phenyl-substituted with R³³; 4-(ethoxy)-phenyl-substituted withR³³; 4-(i-propoxy)-phenyl-substituted with R³³;4-(i-butoxy)-phenyl-substituted with R³³;4-(H₃CCH₂CH₂C(═O))-phenyl-substituted with R³³;4-((H₃C)₂CHC(═O))-phenyl-substituted with R³³;4-(H₃CCH₂C(═O))-phenyl-substituted with R³³;4-(H₃CC(═O))-phenyl-substituted with R³³;4-(H₃CCH₂CH₂CH(OH))-phenyl-substituted with R³³; 4-((H₃C)₂CHCH(OH))-phenyl-substituted with R³³;4-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;4-(H₃CCH(OH))-phenyl-substituted with R³³;4-(cyclopropyloxy)-phenyl-substituted with R³³;4-(cyclobutyloxy)-phenyl-substituted with R³³; and4-(cyclopentyloxy)-phenyl-substituted with R³³; R¹³ is H, methyl, orethyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringselected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl,piperizinyl, methylpiperizinyl,and morpholinyl; alternatively, R¹² andR¹³ when attached to N may be combined to form a 9- or 10-memberedbicyclic heterocyclic ring system containing from 1-3 heteroatomsselected from the group consisting of N, O, and S; wherein said bicyclicheterocyclic ring system is selected from indolyl, indolinyl, indazolyl,benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein saidbicyclic heterocyclic ring system is substituted with 0-1 R¹⁶; R¹⁵ is H,methyl, ethyl, propyl, or butyl; R¹⁶, at each occurrence, isindependently selected from H, OH, F, Cl, CN, NO₂, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R³³, at eachoccurrence, is independently selected from H, F, Cl, —CH₃, —OCH₃, —CF₃,—OCF₃, —CN, and —NO₂; k is 1; m is 1; and n is 1 or
 2. 7. A compound ofclaim 2 of Formula (I-a)

wherein: b is a single bond; X is —NR^(10A)—; R¹ is selected fromhydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-methylpropyl,2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl,3-methylbutyl, 4-methylpentyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl,3-methyl-butenyl, 3-butenyl, trans-2-pentenyl, cis-2-pentenyl,4-pentenyl, 4-methyl-3-pentenyl, 3,3-dichloro-2-propenyl,trans-3-phenyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 2,5-dimethylbenzyl, 2,4-dimethylbenzyl,3,5-dimethylbenzyl, 2,4,6-trimethyl-benzyl, 3-methoxy-benzyl,3,5-dimethoxy-benzyl, pentafluorobenzyl, 2-phenylethyl,1-phenyl-2-propyl, 4-phenylbutyl, 4-phenylbenzyl, 2-phenylbenzyl,(2,3-dimethoxy-phenyl)C(═O)—, (2,5-dimethoxy-phenyl)C(═O)—,(3,4-dimethoxy-phenyl)C(═O)—, (3,5-dimethoxy-phenyl)C(═O)—,cyclopropyl-C(═O)—, isopropyl-C(═O)—, ethyl-CO₂-, propyl-CO₂-,t-butyl-CO₂-, 2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl,2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl, 2,4,5-trimethoxy-benzyl,2,3,4-trimethoxy-benzyl, 3,4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl,(4-fluoro-phenyl)ethyl, —CH═CH₂, —CH₂—CH═CH₂, —CH═CH—CH₃, —C≡—CH,—C≡C—CH₃, and —CH₂—C≡—CH; R⁷, R⁸, and R⁹, at each occurrence, areindependently selected from hydrogen, fluoro, chloro, bromo, cyano,methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl,methylC(═O)—, ethylC(═O)—, propylC(═O)—, isopropylC(═O)—, butylC(═O)—,phenylC(═O)—, methylCO₂-, ethylCO₂-, propylCO₂-, isopropylCO₂-,butylCO₂-, phenylCO₂-, dimethylamino-S(═O)—, diethylamino-S(═O)—,dipropylamino-S(═O)—, di-isopropylamino-S(═O)—, dibutylamino-S(═O)—,diphenylamino-S(═O)—, dimethylamino-SO₂-, diethylamino-SO₂-,dipropylamino-SO₂-, di-isopropylamino-SO₂-, dibutylamino-SO₂-,diphenylamino-SO₂-, dimethylamino-C(═O)—, diethylamino-C(═O)—,dipropylamino-C(═O)—, di-isopropylamino-C(═O)—, dibutylamino-C(═O)—,diphenylamino-C(═O)—, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl,2-trifluoromethoxyphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl, 3-propylphenyl,3-isopropylphenyl, 3-butylphenyl, 3-trifluoromethylphenyl,3-methoxyphenyl, 3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,3-thiomethoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl,4-isopropylphenyl, 4-butylphenyl, 4-trifluoromethylphenyl,4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,4-thiomethoxyphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,3-dimethylphenyl, 2, 3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,2,3-ditrifluoromethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,4-dimethylphenyl, 2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,2,4-ditrifluoromethoxyphenyl, 2,5-dichlorophenyl, 2,5-difluorophenyl,2,5-dimethylphenyl, 2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,2,5-ditrifluoromethoxyphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl,2,6-dimethylphenyl, 2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,2,6-ditrifluoromethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3,4-dimethylphenyl, 3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,3,4-ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl,2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl,2,4,6-tritrifluoromethylphenyl, 2,4,6-trimethoxyphenyl,2,4,6-tritrifluoromethoxyphenyl, 2-chloro-4-CF₃-phenyl,2-fluoro-3-chloro-phenyl, 2-chloro-4-CF₃-phenyl,2-chloro-4-methoxy-phenyl, 2-methoxy-4-isopropyl-phenyl,2-CF₃-4-methoxy-phenyl, 2-methyl-4-methoxy-5-fluoro-phenyl,2-methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl,2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, methyl-C(═O)NH—,ethyl-C(═O)NH—, propyl-C(═O)NH—, isopropyl-C(═O)NH—, butyl-C(═O)NH—,phenyl-C(═O)NH—, 4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl,2-furanyl, 2-thiophenyl, 2-naphthyl; 2-Me-5-F-phenyl, 2-F-5-Me-phenyl,2-MeO-5-F-phenyl, 2-Me-3-Cl-phenyl, 3-NO₂-phenyl, 2-NO₂-phenyl,2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl, 2-Cl-6-F-phenyl,2-Cl-4-(CHF₂)O-phenyl, 2,4-diMeO-6-F-phenyl, 2-CF₃-6-F-phenyl,2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl, 2,3,4-triF-phenyl,2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,2-CF₃-4-EtO-phenyl, 2-CF₃-4-iPrO-phenyl, 2-CF₃-4-Cl-phenyl,2-CF₃-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-C-4-iPrO-phenyl,2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,2-CH(OMe)Me-4-MeO-phenyl, 2-C(═O)Me-4-MeO-phenyl,2-CH₂(OH)-4-MeO-phenyl, 2-CH₂(OMe)-4-MeO-phenyl,2-CH(OH)Et-4-MeO-phenyl, 2-C(═O)Et-4-MeO-phenyl,(Z)-2-CH═CHCO₂Me-4-MeO-phenyl, 2-CH₂CH₂CO₂Me-4-MeO-phenyl,(Z)-2-CH═CHCH₂(OH)-4-MeO-phenyl, (E)-2-CH═CHCO₂Me-4-MeO-phenyl,(E)-2-CH═CHCH₂(OH)-4-MeO-phenyl, 2-CH₂CH₂OMe-4-MeO-phenyl,2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl, (2-Cl-phenyl)-CH═CH—,(3-Cl-phenyl)-CH═CH—, (2,6-diF-phenyl)-CH═CH—, —CH₂CH═CH₂,phenyl-CH═CH—, (2-Me-4-MeO-phenyl)-CH═CH—, cyclohexyl, cyclopentyl,cyclohexylmethyl, —CH₂CH₂CO₂Et, —(CH₂)₃CO₂Et, —(CH₂)₄CO₂Et, benzyl,2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,2-MeO-benzyl, 2-OH-benzyl, 2-CO₂Me-3-MeO-phenyl, 2-Me-4-CN-phenyl,2-Me-3-CN-phenyl, 2-CF₃-4-CN-phenyl, 3-CHO-phenyl, 3-CH₂(OH)-phenyl,3-CH₂(OMe)-phenyl, 3-CH₂(NMe₂)-phenyl, 3-CN-4-F-phenyl,3-CONH₂-4-F-phenyl, 2-CH₂(NH₂)-4-MeO-phenyl-, phenyl-NH—,(4-F-phenyl)-NH—, (2,4-diCl-phenyl)-NH—, phenyl-C(═O)NH—, benzyl-NH—,(2-Me-4-MeO-phenyl)-NH—, (2-F-4-MeO-phenyl)-NH—, (2-Me-4-F-phenyl)-NH—,phenyl-S—, —NMe₂, 1-pyrrolidinyl, and —N(tosylate)₂, provided that twoof R⁷, R⁸, and R⁹, are independently selected from hydrogen, fluoro,chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl,nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, andtrifluoromethoxy; R^(10A) is selected from hydrogen, methyl, ethyl,benzyl and 4-fluorobenzyl; m is 1; and n is 1 or
 2. 8. A compound ofclaim 7 of Formula (IV)

wherein: b is a single bond, wherein the bridge hydrogens are in a cisposition; R¹ is selected from hydrogen, methyl, ethyl, n-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl,2-pentyl, 2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl,2-ethylbutyl, 3-methylpentyl, 3-methylbutyl, 4-methylpentyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, —CH═CH₂,—CH₂—CH═CH₂, —CH═CH—CH₃, —C≡CH, —C≡C—CH₃, and —CH₂—C≡CH; R⁷ and R⁹, ateach occurrence, are independently selected from hydrogen, fluoro,methyl, trifluoromethyl, and methoxy; R⁸ is selected from hydrogen,fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl,t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy,trifluoromethoxy, phenyl, methylC(═O)—, ethylC(═O)—, propylC(═O)—,isopropylC(═O)—, butylC(═O)—, phenylC(═O)—, methylCO₂—, ethylCO₂—,propylCO₂—, isopropylCO₂—, butylCO₂—, phenylCO₂—, dimethylamino-S(═O)—,diethylamino-S(═O)—, dipropylamino-S(═O)—, di-isopropylamino-S(═O)—,dibutylamino-S(═O)—, diphenylamino-S(═O)—, dimethylamino-SO₂—,diethylamino-SO₂—, dipropylamino-SO₂—, di-isopropylamino-SO₂—,dibutylamino-SO₂—, diphenylamino-SO₂—, dimethylamino-C(═O)—,diethylamino-C(═O)—, dipropylamino-C(═O)—, di-isopropylamino-C(═O)—,dibutylamino-C(═O)—, diphenylamino-C(═O)—, 2-chlorophenyl,2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl, 2-methylphenyl,2-trifluoromethylphenyl, 2-methoxyphenyl, 2-trifluoromethoxyphenyl,3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-cyanophenyl,3-methylphenyl, 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl,3-butylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,3-isopropoxyphenyl, 3-trifluoromethoxyphenyl, 3-thiomethoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl,4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl,4-butylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,4-isopropoxyphenyl, 4-trifluoromethoxyphenyl, 4-thiomethoxyphenyl,2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,2,3-ditrifluoromethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,4-dimethylphenyl, 2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,2,4-ditrifluoromethoxyphenyl, 2,5-dichlorophenyl, 2,5-difluorophenyl,2,5-dimethylphenyl, 2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,2,5-ditrifluoromethoxyphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl,2,6-dimethylphenyl, 2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,2,6-ditrifluoromethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3,4-dimethylphenyl, 3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,3,4-ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl,2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl,2,4,6-tritrifluoromethylphenyl, 2,4,6-trimethoxyphenyl,2,4,6-tritrifluoromethoxyphenyl, 2-chloro-4-CF₃-phenyl,2-fluoro-3-chloro-phenyl, 2-chloro-4-CF₃-phenyl,2-chloro-4-methoxy-phenyl, 2-methoxy-4-isopropyl-phenyl,2-CF₃-4-methoxy-phenyl, 2-methyl-4-methoxy-5-fluoro-phenyl,2-methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl,2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, methyl-C(═O)NH—,ethyl-C(═O)NH—, propyl-C(═O)NH—, isopropyl-C(═O)NH—, butyl-C(═O)NH—,phenyl-C(═O)NH—, 4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl,2-furanyl, 2-thiophenyl, 2-naphthyl; 2-Me-5-F-phenyl, 2-F-5-Me-phenyl,2-MeO-5-F-phenyl, 2-Me-3-Cl-phenyl, 3-NO₂-phenyl, 2-NO₂-phenyl,2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl, 2-Cl-6-F-phenyl,2-Cl-4-(CHF₂)O-phenyl, 2,4-diMeO-6-F-phenyl, 2-CF₃-6-F-phenyl,2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl, 2,3,4-triF-phenyl,2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,2-CF₃-4-EtO-phenyl, 2-CF₃-4-iPrO-phenyl, 2-CF₃-4-Cl-phenyl,2-CF₃-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,2-CH(OMe)Me-4-MeO-phenyl, 2-C(═O)Me-4-MeO-phenyl,2-CH₂(OH)-4-MeO-phenyl, 2-CH₂(OMe)-4-MeO-phenyl,2-CH(OH)Et-4-MeO-phenyl, 2-C(═O)Et-4-MeO-phenyl,(Z)-2-CH═CHCO₂Me-4-MeO-phenyl, 2-CH₂CH₂CO₂Me-4-MeO-phenyl,(Z)-2-CH═CHCH₂(OH)-4-MeO-phenyl, (E)-2-CH═CHC₂Me-4-MeO-phenyl,(E)-2-CH═CHCH₂(OH)-4-MeO-phenyl, 2-CH₂CH₂OMe-4-MeO-phenyl,2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl, (2-Cl-phenyl)-CH═CH—,(3-Cl-phenyl)-CH═CH—, (2,6-diF-phenyl)-CH═CH—, —CH₂CH═CH₂,phenyl-CH═CH—, (2-Me-4-MeO-phenyl)-CH═CH—, cyclohexyl, cyclopentyl,cyclohexylmethyl, —CH₂CH₂CO₂Et, —(CH₂)₃CO₂Et, —(CH₂)₄CO₂Et, benzyl,2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,2-MeO-benzyl, 2-OH-benzyl, 2-CO₂Me-3-MeO-phenyl, 2-Me-4-CN-phenyl,2-Me-3-CN-phenyl, 2-CF₃-4-CN-phenyl, 3-CHO-phenyl, 3-CH₂(OH)-phenyl,3-CH₂(OMe)-phenyl, 3-CH₂(NMe₂)-phenyl, 3-CN-4-F-phenyl,3-CONH₂-4-F-phenyl, 2-CH₂(NH₂)-4-MeO-phenyl-, phenyl-NH—,(4-F-phenyl)-NH—, (2,4-diCl-phenyl)-NH—, phenyl-C(═O)NH—, benzyl-NH—,(2-Me-4-MeO-phenyl)-NH—, (2-F-4-MeO-phenyl)-NH—, (2-Me-4-F-phenyl)-NH—,phenyl-S—, —NMe₂, 1-pyrrolidinyl, and —N(tosylate)₂; R^(10A) is selectedfrom hydrogen, methyl, ethyl, 4-fluorobenzyl and benzyl; and n is 1 or2.
 9. A compound of claim 1 wherein: X is —NR^(10A)—; R¹ is selectedfrom C₁₋₆ alkyl substituted with Z, C₂₋₆ alkenyl substituted with Z,C₂₋₆ alkynyl substituted with Z, C₃₋₆ cycloalkyl substituted with Z,aryl substituted with Z, 5-6 membered heterocyclic ring systemcontaining at least one heteroatom selected from the group consisting ofN, O, and S, said heterocyclic ring system substituted with Z; C₁₋₆alkyl substituted with 0-2 R², C₂₋₆ alkenyl substituted with 0-2 R²,C₂₋₆ alkynyl substituted with 0-2 R², aryl substituted with 0-2 R², and5-6 membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with 0-2 R²; Z is selected from H, —CH(OH)R²,—C(ethylenedioxy)R², —OR², —SR², —NR²R³, —C(O) R², —C(O)NR²R³,—NR³C(O)R², —C(O)OR², —OC(O)R², —CH(═NR⁴)NR²R³, —NHC(═NR⁴)NR²R³,—S(O)R², —S(O)₂R², —S(O)₂NR²R³, and —NR³S(O)₂R²; R², at each occurrence,is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₆ cycloalkyl, aryl substituted with 0-5 R⁴²; C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R⁴¹, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴¹; R³, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,and C₁₋₄ alkoxy; alternatively, R² and R³ join to form a 5- or6-membered ring optionally substituted with —O— or —N(R⁴)—; R⁴, at eachoccurrence, is independently selected from H, methyl, ethyl, propyl, andbutyl; R⁵ is H, methyl, ethyl, propyl, or butyl; R^(6a) is selected fromH, —OH, —NR⁴⁶R⁴⁷, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, and aryl substituted with 0-3R⁴⁴; R^(6b) is H; R⁷, R⁸, and R⁹, at each occurrence, are independentlyselected from H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy, (C₁₋₄haloalkyl)oxy, C₁₋₄ alkyl substituted with 0-2 R¹¹, C₃₋₁₀ carbocyclicgroup substituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹²,C(O)OR¹², OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³,S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O) R¹²,NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, andNR¹²C(O)NHR¹⁵; R^(10A) is selected from H, C₁₋₆ alkyl substituted with0-1 R^(10B), C₂₋₆ alkenyl substituted with 0-1 R^(10B), C₂₋₆ alkynylsubstituted with 0-1 R^(10B), and C₁₋₆ alkoxy; R^(10B) is selected fromC₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₁₀ carbocyclic group substituted with0-3 R³³, phenyl substituted with 0-3 R³³, and 5-6 membered heterocyclicring system containing 1, 2, or 3 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-2 R⁴⁴; R¹¹ is selected fromH, halo, —CF₃, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; OR¹²,SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R12,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²; R¹²,at each occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, phenyl substituted with 0-5 R³³;C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; R¹³, ateach occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl; alternatively, R¹² and R¹³ join to form a 5-or 6-membered ring optionally substituted with —O— or —N(R¹⁴)—; R¹⁴, ateach occurrence, is independently selected from H and C₁₋₄ alkyl; R³¹,at each occurrence, is independently selected from H, OH, halo, CF₃,SO₂R⁴⁵, NR⁴⁶R⁴⁷, methyl, ethyl, and propyl; R³³, at each occurrence, isindependently selected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷,C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₃₋₅ cycloalkyl, C₁₋₃ haloalkyl,C₁₋₃ haloalkyl-oxy-, C₁₋₃ alkyloxy-, C₁₋₃ alkylthio-, C₁₋₃ alkyl-C(═O)—,and C₁₋₃ alkyl-C(═O)NH—; R⁴¹, at each occurrence, is independentlyselected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl C₁₋₄ alkylsubstituted with 0-1 R⁴³, aryl substituted with 0-3 R⁴², and 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴; R⁴², at each occurrence, is independently selected from H, CF₃,halo, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-1 R⁴³, aryl substitutedwith 0-3 R⁴⁴, and 5-10 membered heterocyclic ring system containing from1-4 heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴; R⁴³ is C₃₋₆ cycloalkyl or aryl substitutedwith 0-3 R⁴⁴; R⁴⁴, at each occurrence, is independently selected from H,halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl,and C₁₋₄ alkoxy; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶, at each occurrence, isindependently selected from H and C₁₋₄ alkyl; R⁴⁷, at each occurrence,is independently selected from H, C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl),—SO₂(C₁₋₄ alkyl), —SO₂(phenyl), —C(═O)O(C₁₋₄ alkyl), —C(═O) (C₁₋₄alkyl), and —C(═O)H; R⁴⁸, at each occurrence, is independently selectedfrom H, C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl), —C(═O)(C₁₋₄ alkyl), and —C(═O)H; k is 1 or 2; m is 0, 1, or 2; and n is 1 or2.
 10. A compound of claim 9 wherein: X is —NR^(10A)—; R¹ is selectedfrom C₂₋₅ alkyl substituted with Z, C₂₋₅ alkenyl substituted with Z,C₂₋₅ alkynyl substituted with Z, C₃₋₆ cycloalkyl substituted with Z,aryl substituted with Z, 5-6 membered heterocyclic ring systemcontaining at least one heteroatom selected from the group consisting ofN, O, and S, said heterocyclic ring system substituted with Z; C₁₋₅alkyl substituted with 0-2 R², C₂₋₅ alkenyl substituted with 0-2 R², andC₂₋₅ alkynyl substituted with 0-2 R²; Z is selected from H, —CH(OH)R²,—C(ethylenedioxy)R², —OR², —SR², —NR²R³, —C(O) R², —C(O) NR²R³,—NR³C(O)R², —C(O) OR², —OC(O)R², —CH(═NR⁴)NR²R³, —NHC(═NR⁴)NR²R³,—S(O)R², —S(O)₂R², —S(O)₂NR²R³, and —NR³S(O)₂R²; R², at each occurrence,is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₆ cycloalkyl, aryl substituted with 0-5 R⁴²; C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R⁴¹, and 5-10 membered heterocyclic ring systemcontaining from, 1-4 heteroatoms selected from the group consisting ofN, O, and S substituted with 0-3 R⁴¹; R³, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,and C₁₋₄ alkoxy; alternatively, R² and R³ join to form a 5- or6-membered ring optionally substituted with —O— or —N(R⁴)—; R⁴, at eachoccurrence, is independently selected from H, methyl, ethyl, propyl, andbutyl; R⁵ is H, methyl, or ethyl; R^(6a) is selected from H, —OH,—NR⁴⁶R⁴⁷, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, and C₃₋₆ cycloalkyl; R^(6b) is H; R⁷, R⁸, and R⁹, ateach occurrence, are independently selected from H, halo, —CF₃, —OCF₃,—OH, —OCH₃, —CN, —NO₂, —NR⁴⁶R⁴⁷, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₄ haloalkyl, C₁₋₆ alkoxy, (C₁₋₄ haloalkyl)oxy, C₁₋₄ alkyl substitutedwith 0-2 R¹¹, C₃₋₁₀ carbocyclic group substituted with 0-3 R³³, arylsubstituted with 0-5 R³³, 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², CH(═NR¹⁴)NR¹²R¹³,NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)₂NR¹²R¹³, NR¹⁴S(O)₂R¹²,NR¹⁴S(O)R¹², NR¹⁴S(O) ₂R¹², NR¹²C(O) R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵,and NR¹²C(O)NHR¹⁵; R^(10A) is selected from H, C₁₋₆ alkyl substitutedwith 0-1 R^(10B), C₂₋₆ alkenyl substituted with 0-1 R^(10B), C₂₋₆alkynyl substituted with 0-1 R^(10B), and C₁₋₆ alkoxy; R^(10B) isselected from C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆ carbocyclic groupsubstituted with 0-3 R³³, phenyl substituted with 0-3 R³³, and 5-6membered heterocyclic ring system containing 1, 2, or 3 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴⁴; R¹¹ is selected from H, halo, —CF₃, —OCF₃, —OH, —OCH₃, —CN, —NO₂,—NR⁴⁶R⁴⁷, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₆alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ carbocyclic group substituted with0-3 R³³, aryl substituted with 0-5 R³³, 5-10 membered heterocyclic ringsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³,C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹² _(,) C(O)OR¹², OC(O)R¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R^(13, S(O)R) ¹², S(O)₂R¹²,S(O)₂NR¹²R¹³, and NR¹⁴S(O)₂R¹²; R¹², at each occurrence, isindependently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, phenyl substituted with 0-5 R³³; C₃₋₁₀ carbocyclic groupsubstituted with 0-3 R³³, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; R¹³, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—; R¹⁴, at each occurrence, isindependently selected from H and C₁₋₄ alkyl; R³¹, at each occurrence,is independently selected from H, OH, halo, CF₃, methyl, and ethyl; R³³,at each occurrence, is independently selected from H, OH, halo, CN, NO₂,CF₃, methyl, and ethyl; R⁴¹, at each occurrence, is independentlyselected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ alkylsubstituted with 0-1 R⁴³, aryl substituted with 0-3 R⁴², and 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴; R⁴², at each occurrence, is independently selected from H, CF₃,halo, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-1 R⁴³, aryl substitutedwith 0-3 R⁴⁴, and 5-10 membered heterocyclic ring system containing from1-4 heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴; R⁴³ is C₃₋₆ cycloalkyl or aryl substitutedwith 0-3 R⁴⁴; R⁴⁴, at each occurrence, is independently selected from H,halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl,and C₁₋₄ alkoxy; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶, at each occurrence, isindependently selected from H and C₁₋₃ alkyl; R⁴⁷, at each occurrence,is independently selected from H, C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl),—SO₂(C₁₋₄ alkyl), —SO₂(phenyl), —C(═O)O(C₁₋₄ alkyl), —C(═O) (C₁₋₄alkyl), and —C(═O)H; R⁴⁸, at each occurrence, is independently selectedfrom H, C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl), —C(═O)(C₁₋₄ alkyl), and —C(═O)H; k is 1 or 2; m is 0, 1, 2; and n is 1 or 2.11. A compound of claim 9 wherein: X is —NR^(10A)—; R¹ i s selected fromC₂₋₄ alkyl substituted with Z, C₂₋₄ alkenyl substituted with Z, C₂₋₄alkynyl substituted with Z, C₃₋₆ cycloalkyl substituted with Z, arylsubstituted with Z, 5-6 membered heterocyclic ring system containing atleast one heteroatom selected from the group consisting of N, O, and S,said heterocyclic ring system substituted with Z; C₂₋₄ alkyl substitutedwith 0-2 R², and C₂₋₄ alkenyl substituted with 0-2 R²; Z is selectedfrom H, —CH(OH)R², —C(ethylenedioxy)R², —OR², —SR², —NR²R³, —C(O)R²,—C(O)NR²R³, —NR³C(O)R², —C(O)OR², —S(O)R², —S(O)₂R², —S(O)₂NR²R³, and—NR³S(O)₂R²; R², at each occurrence, is independently selected fromphenyl substituted with 0-5 R⁴²; C₃₋₁₀ carbocyclic group substitutedwith 0-3 R⁴¹, and 5-10 membered heterocyclic ring system containing from1-4 heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹; R³, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄alkoxy; alternatively, R² and R³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R⁴)—; R⁴, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, and butyl; R⁵ isH; R^(6a) is selected from H, —OH, —CF₃, methyl, ethyl, propyl, butyl,methoxy, and, ethoxy; R^(6b) is H; R⁷, R⁸, and R⁹, at each occurrence,are independently selected from H, halo, —CF₃, —OCF₃, —OH, —OCH₃, —CN,—NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, (C₁₋₃ haloalkyl)oxy, andC₁₋₄ alkyl substituted with 0-2 R¹¹; R^(10A) is selected from H, C₁₋₆alkyl, C₁₋₄ alkoxy, and C₁₋₂ alkyl substituted with 0-1 R^(10B); R^(10B)is C₃₋₆ cycloalkyl or phenyl substituted with 0-3 R³³; R¹¹ is selectedfrom H, halo, —CF₃, —OCF₃, —OH, —OCH₃, —CN, —NO₂, C₁₋₄ alkyl, , C₁₋₄haloalkyl, C₁₋₄ alkoxy, and (C₁₋₃ haloalkyl)oxy; R³³, at eachoccurrence, is independently selected from H, OH, halo, CF₃, and methyl;R⁴¹, at each occurrence, is independently selected from H, CF₃, halo,OH, CF₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ alkyl substituted with 0-1 R⁴³, arylsubstituted with 0-3 R⁴², and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴⁴; R⁴², at each occurrence, isindependently selected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵,NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkylsubstituted with 0-1 R⁴³, aryl substituted with 0-3 R⁴⁴, and 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴; R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, orpyridyl, each substituted with 0-3 R⁴⁴; R⁴⁴, at each occurrence, isindependently selected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —SF₃,—OCF₃, —CN, —NO₂, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, and butoxy; R⁴⁵ is methyl, ethyl, propyl, or butyl; R⁴⁶, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; R⁴⁷, at each occurrence, is independently selectedfrom H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,—C(═O)NH(methyl), —C(═O)NH(ethyl), —SO₂(methyl), —SO₂(ethyl),—SO₂(phenyl), —C(═O)O(methyl), —C(═O)O(ethyl), —C(═O)(methyl),—C(═O)(ethyl), and —C(═O)H; R⁴⁸, at each occurrence, is independentlyselected from H, methyl, ethyl, n-propyl, i-propyl, —C(═O)NH(methyl),—C(═O)NH(ethyl), —C(═O)O(methyl), —C(═O)O(ethyl), —C(═O) (methyl),—C(═O) (ethyl), and —C(═O)H; k is 1; m is 0, 1, or 2; and n is 1 or 2.12. A compound of claim 9 wherein: X is —NH—; R¹ is selected from ethylsubstituted with Z, propyl substituted with Z, butyl substituted with Z,propenyl substituted with Z, butenyl substituted with Z, ethylsubstituted with R², propyl substituted with R², butyl substituted withR², propenyl substituted with R² and butenyl substituted with R²; Z isselected from H, —HC(OH) R², —SR², —NR²R³, —C(O)R², —C(O)NR²R³, —NR³C(O)R², —C(O)OR², —S(O)R², —S(O)₂R², —S(O)₂NR²R³, and —NR³S(O)₂R²; R², ateach occurrence, is independently selected from phenyl substituted with0-3 R⁴²; naphthyl substituted with 0-3 R⁴²; cyclopropyl substituted with0-3 R⁴¹; cyclobutyl substituted with 0-3 R⁴¹; cyclopentyl substitutedwith 0-3 R⁴¹; cyclohexyl substituted with 0-3 R⁴¹; pyridyl substitutedwith 0-3 R⁴¹; indolyl substituted with 0-3 R⁴¹; indolinyl substitutedwith 0-3 R⁴¹; benzimidazolyl substituted with 0-3 R⁴¹; benzotriazolylsubstituted with 0-3 R⁴¹; benzothienyl substituted with 0-3 R⁴¹;benzofuranyl substituted with 0-3 R⁴¹; phthalimid-1-yl substituted with0-3 R⁴¹; inden-2-yl substituted with 0-3 R⁴¹; 2,3-dihydro-1H-inden-2-ylsubstituted with 0-3 R⁴¹; indazolyl substituted with 0-3 R⁴¹;tetrahydroquinolinyl substituted with 0-3 R⁴¹; andtetrahydro-isoquinolinyl substituted with 0-3 R⁴¹; R³, at eachoccurrence, is independently selected from H, methyl, and ethyl; R⁵ isH; R^(6a) is selected from H, —OH, methyl, and methoxy; R^(6b) is H; R⁷,R⁸, and R⁹, at each occurrence, are independently selected from H, F,Cl, methyl, ethyl, methoxy, —CF₃, and —OCF₃; R⁴¹, at each occurrence, isindependently selected from H, F, Cl, Br, OH, CF₃, NO₂, CN, ═O, methyl,ethyl, propyl, butyl, methoxy, and ethoxy; R⁴², at each occurrence, isindependently selected from H, F, Cl, Br, OH, CF₃, SO₂R⁴⁵, SR⁴⁵,NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, ═O, methyl, ethyl, propyl, butyl, methoxy, andethoxy; R⁴⁵ is methyl, ethyl, propyl, or butyl; R⁴⁶, at each occurrence,is independently selected from H, methyl, ethyl, propyl, and butyl; R⁴⁷,at each occurrence, is independently selected from H, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, —C(═O)NH(methyl), —C(═O)NH(ethyl),—SO₂(methyl), —SO2(ethyl), —SO2(phenyl), —C(═O)O(methyl),—C(═O)O(ethyl), —C(═O)(methyl), —C(═O)(ethyl), and —C(═O)H; R⁴⁸, at eachoccurrence, is independently selected from H, methyl, ethyl, n-propyl,i-propyl, —C(═O)NH(methyl), —C(═O)NH(ethyl), —C(═O)O(methyl),—C(═O)O(ethyl), —C(═O)(methyl), —C(═O)(ethyl), and —C(═O)H; k is 1; m is0, 1, or 2; and n is 1 or
 2. 13. A compound of claim 9 of Formula (I-a)

wherein: b is a single bond; X is —NR^(10A)—; R¹ is selected from—(CH₂)₃C(═O)(4-fluoro-phenyl), —(CH₂)₃C(═O)(4-bromo-phenyl),—(CH₂)₃C(═O)(4-methyl-phenyl), —(CH₂)₃C(═O)(4-methoxy-phenyl),—(CH₂)₃C(═O)(4-(3,4-dichloro-phenyl)phenyl),—(CH₂)₃C(═O)(3-methyl-4-fluoro-phenyl),—(CH₂)₃C(═O)(2,3-dimethoxy-phenyl), —(CH₂)₃C(═O)(phenyl),—(CH₂)3C(═O)(4-chloro-phenyl), —(CH₂)₃C(═O)(3-methyl-phenyl),—(CH₂)₃C(═O)(4-t-butyl-phenyl), —(CH₂)₃C(═O)(3,4-difluoro-phenyl),—(CH₂)₃C(═O)(2-methoxy-5-fluoro-phenyl),—(CH₂)₃C(═O)(4-fluoro-1-naphthyl), —(CH₂)₃C(═O)(benzyl),—(CH₂)₃C(═O)(4-pyridyl), —(CH₂)₃C(═O)(3-pyridyl),—(CH₂)₃CH(OH)(4-fluoro-phenyl), —(CH₂)₃CH(OH)(4-pyridyl),—(CH₂)₃CH(OH)(2,3-dimethoxy-phenyl), —(CH₂)₃S(3-fluoro-phenyl),—(CH₂)₃S(4-fluoro-phenyl), —(CH₂)₃S(═O)(4-fluoro-phenyl),—(CH₂)₃SO₂(3-fluoro-phenyl), —(CH₂)₃SO₂(4-fluoro-phenyl),—(CH₂)₃O(4-fluoro-phenyl), —(CH₂)₃O(phenyl), —(CH₂)₃O(3-pyridyl),—(CH₂)₃O(4-pyridyl), —(CH₂)₃O(2-NH₂-phenyl), —(CH₂)₃O(2-NH₂-5-F-phenyl),—(CH₂)₃O(2-NH₂-4-F-phenyl), —(CH₂)₃O(2-NH₂-3-F-phenyl),—(CH₂)₃O(2-NH₂-4-Cl-phenyl), —(CH₂)₃O(2-NH₂-4-OH-phenyl),—(CH₂)₃O(2-NH₂-4-Br-phenyl), —(CH₂)₃O(2-NHC(═O)Me-4-F-phenyl),—(CH₂)₃O(2-NHC(═O)Me-phenyl), —(CH₂)₃NH(4-fluoro-phenyl), —(CH₂)₃N(methyl)(4-fluoro-phenyl), —(CH₂)₃CO₂(ethyl),—(CH₂)₃C(═O)N(methyl)(methoxy), —(CH₂)₃C(═O)NH(4-fluoro-phenyl),—(CH₂)₂NHC(═O)(phenyl), —(CH₂)₂NMeC(═O)(phenyl),—(CH₂)₂NHC(═O)(2-fluoro-phenyl), —(CH₂)₂NMeC(═O)(2-fluoro-phenyl),—(CH₂)₂NHC(═O)(4-fluoro-phenyl), —(CH₂)₂NMeC(═O)(4-fluoro-phenyl),—(CH₂)₂NHC(═O)(2,4-difluoro-phenyl),—(CH₂)₂NMeC(═O)(2,4-difluoro-phenyl), —(CH₂)₃(3-indolyl),—(CH₂)₃(1-methyl-3-indolyl), —(CH₂)₃(1-indolyl), —(CH₂)₃(1-indolinyl),—(CH₂)₃(1-benzimidazolyl), —(CH₂)₃(1H-1,2,3-benzotriazol-1-yl),—(CH₂)₃(1H-1,2,3-benzotriazol-2-yl),—(CH₂)₂(1H-1,2,3-benzotriazol-1-yl),—(CH₂)₂(1H-1,2,3-benzotriazol-2-yl), —(CH₂)₃(3,4dihydro-1(2H)-quinolinyl), —(CH₂)₂C(═O)(4-fluoro-phenyl),—(CH₂)₂C(═O)NH(4-fluoro-phenyl), —CH₂CH₂(3-indolyl),—CH₂CH₂(1-phthalimidyl), —(CH₂)₄C(═O)N(methyl)(methoxy),—(CH₂)₄CO₂(ethyl), —(CH₂)₄C(═O)(phenyl), —(CH₂)₄(cyclohexyl),—(CH₂)₃CH(phenyl)₂, —CH₂CH₂CH═C(phenyl)₂, —CH₂CH₂CH═CMe(4-F-phenyl),—(CH₂)₃CH(4-fluoro-phenyl)₂, —CH₂CH₂CH═C(4-fluoro-phenyl)₂,—(CH₂)₂(2,3-dihydro-1H-inden-2-yl), —(CH₂)₃C(═O)(2-NH₂-phenyl),—(CH₂)₃C(═O)(2-NH₂-5-F-phenyl), —(CH₂)₃C(═O)(2-NH₂-4-F-phenyl),—(CH₂)₃C(═O)(2-NH₂-3-F-phenyl), —(CH₂)₃C(═O)(2-NH₂-4-Cl-phenyl),—(CH₂)₃C(═O)(2-NH₂-4-OH-phenyl), —(CH₂)₃C(═O)(2-NH₂-4-Br-phenyl),—(CH₂)₃(1H-indazol-3-yl), —(CH₂)₃(5-F-1H-indazol-3-yl),—(CH₂)₃(7-F-1H-indazol-3-yl), —(CH₂)₃(6-Cl-1H-indazol-3-yl),—(CH₂)₃(6-Br-1H-indazol-3-yl), —(CH₂)₃C(═O)(2-NHMe-phenyl),—(CH₂)₃(1-benzothien-3-yl), —(CH₂)₃(6-F-1H-indol-1-yl),—(CH₂)₃(5-F-1H-indol-1-yl), —(CH₂)₃(6-F-2,3-dihydro-1H-indol-1-yl),—(CH₂)₃(5-F-2,3-dihydro-1H-indol-1-yl), —(CH₂)₃(6-F-1H-indol-3-yl),—(CH₂)₃(5-F-1H-indol-3-yl), —(CH₂)₃(5-F-1H-indol-3-yl),—(CH₂)₃(9H-purin-9-yl), —(CH₂)₃(7H-purin-7-yl),—(CH₂)₃(6-F-1H-indazol-3-yl), —(CH₂)₃C(═O)(2-NHSO₂Me-4-F-phenyl),—(CH₂)₃C(═O)(2-NHC(═O)Me-4-F-phenyl), —(CH₂)₃C(═O)(2-NHC(═O)Me-phenyl),—(CH₂)₃C(═O)(2-NHCO₂Et-4-F-phenyl),—(CH₂)₃C(═O)(2-NHC(═O)NHEt-4-F-phenyl),—(CH₂)₃C(═O)(2-NHCHO-4-F-phenyl), —(CH₂)₃C(═O)(2-OH-4-F-phenyl),—(CH₂)₃C(═O)(2-MeS-4-F-phenyl), —(CH₂)₃C(═O)(2-NHSO₂Me-4-F-phenyl),—(CH₂)₂C(Me)CO₂Me, —(CH₂)₂C(Me)CH(OH)(4-F-phenyl)₂,—(CH₂)₂C(Me)CH(OH)(4-Cl-phenyl)₂, —(CH₂)₂C(Me)C(═O)(4-F-phenyl),—(CH₂)₂C(Me)C(═O)(2-MeO-4-F-phenyl), —(CH₂)₂C(Me)C(═O)(3-Me-4-F-phenyl),—(CH₂)₂C(Me)C(═O)(2-Me-phenyl), —(CH₂)₂C(Me) C(═O)phenyl,

R⁷, R⁸, and R⁹, at each occurrence, are independently selected fromhydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,isopropoxy, trifluoromethoxy, phenyl, benzyl, HC(═O)—, methylC(═O)—,ethylC(═O)—, propylC(═O)—, isopropylC(═O)—, n-butylC(═O)—,isobutylC(═O)—, secbutylC(═O)—, tertbutylC(═O)—, phenylC(═O)—,methylC(═O)NH—, ethylC(═O)NH—, propylC(═O)NH—, isopropylC(═O)NH—,n-butylC(═O)NH—, isobutylC(═O)NH—, secbutylC(═O)NH—, tertbutylC(═O)NH—,phenylC(═O)NH—, methylamino-, ethylamino-, propylamino-,isopropylamino-, n-butylamino-, isobutylamino-, secbutylamino-,tertbutylamino-, phenylamino-, provided that two of substituents R⁷, R⁸,and R⁹, are independently selected from hydrogen, fluoro, chloro, bromo,cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy;R^(10A) is selected from hydrogen, methyl, ethyl, propyl, isopropyl,butyl, benzyl, 2-chlorobenzyl, 2-fluorobenzyl, 2-bromobenzyl,2-methylbenzyl, 2-trifluoromethylbenzyl, 2-methoxybenzyl,2-trifluoromethoxybenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-bromobenzyl,3-methylbenzyl, 3-trifluoromethylbenzyl, 3-methoxybenzyl,3-trifluoromethoxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl,4-methylbenzyl, 4-trifluoromethylbenzyl, 4-methoxybenzyl, and4-trifluoromethoxybenzyl; k is 1 or 2; m is 1 or 2; and n is 1 or
 2. 14.A compound of claim 13 of Formula (IV-a)

wherein: b is a single bond, wherein the bridge hydrogens are in a cisposition; R¹ is selected from —(CH₂)₃C(═O) (4-fluoro-phenyl),—(CH₂)₃C(═O) (4-bromo-phenyl), —(CH₂)3C(═O) (4-methyl-phenyl),—(CH₂)₃C(═O) (4-methoxy-phenyl),—(CH₂)₃C(═O)(4-(3,4-dichloro-phenyl)phenyl), —(CH₂)₃C(═O)(3-methyl-4-fluoro-phenyl), —(CH₂)₃C(═O) (2,3-dimethoxy-phenyl),—(CH₂)₃C(═O) (phenyl), —(CH₂)₃C(═O) (4-chloro-phenyl), —(CH₂)₃C(═O)(3-methyl-phenyl), —(CH₂)₃C(═O) (4-t-butyl-phenyl), —(CH₂)₃C(═O)(3,4-difluoro-phenyl), —(CH₂)₃C(═O) (2-methoxy-5-fluoro-phenyl),—(CH₂)₃C(═O) (4-fluoro-1-naphthyl), —(CH₂)₃C(═O) (benzyl), —(CH₂)₃C(═O)(4-pyridyl), —(CH₂)₃C(═O) (3-pyridyl), —(CH₂)₃CH(OH) (4-fluoro-phenyl),—(CH₂)₃CH(OH) (4-pyridyl), —(CH₂)₃CH(OH) (2,3-dimethoxy-phenyl),—(CH₂)₃S(3-fluoro-phenyl), —(CH₂)₃S(4-fluoro-phenyl), —(CH₂)₃S(═O)(4-fluoro-phenyl), —(CH₂)₃SO₂(3-fluoro-phenyl), —(CH₂)₃SO₂)(4-fluoro-phenyl), —(CH₂)₃O(4-fluoro-phenyl), —(CH₂)₃O(phenyl),—(CH₂)₃NH(4-fluoro-phenyl), —(CH₂)₃N(methyl) (4-fluoro-phenyl),—(CH₂)₃CO₂(ethyl), —(CH₂)₃C(═O)N(methyl) (methoxy),—(CH₂)₃C(═O)NH(4-fluoro-phenyl), —(CH₂)₂NHC(═O) (phenyl),—(CH₂)₂NMeC(═O) (phenyl), —(CH₂)₂NHC(═O) (2-fluoro-phenyl),—(CH₂)₂NMeC(═O) (2-fluoro-phenyl), —(CH₂)₂NHC(═O) (4-fluoro-phenyl),—(CH₂)₂NMeC(═O) (4-fluoro-phenyl), —(CH₂)₂NHC(═O) (2,4-difluoro-phenyl),—(CH₂)₂NMeC(═O) (2,4-difluoro-phenyl), —(CH₂)₃(3-indolyl)—(CH₂)3(1-methyl-3-indolyl), —(CH₂)₃(1-indolyl), —(CH₂)₃(1-indolinyl),—(CH₂)₃(1-benzimidazolyl), —(CH₂)₃(1H-1,2,3-benzotriazol-1-yl),—(CH₂)₃(1H-1,2,3-benzotriazol-2-yl), —(CH₂)₂(1H-1,2,3-benzotriazol-1-yl) —(CH₂)₂(1H-1,2,3-benzotriazol-2-yl),—(CH₂)₃(3,4 dihydro-1(2H)-quinolinyl), —(CH₂)₂C(═O) (4-fluoro-phenyl),—(CH₂)₂C(═O)NH(4-fluoro-phenyl), —CH₂CH₂(3-indolyl),—CH₂CH₂(1-phthalimidyl), —(CH₂)₄C(═O)N(methyl) (methoxy),—(CH₂)₄CO₂(ethyl), —(CH₂)₄C(═O) (phenyl), —(CH₂)₄(cyclohexyl),—(CH₂)₃CH(phenyl)₂, —CH₂CH₂CH═C(phenyl)₂, —CH₂CH₂CH═CMe(4-F-phenyl),—(CH₂)₃CH(4-fluoro-phenyl)₂, —CH₂CH₂CH═C(4-fluoro-phenyl)₂, —(CH₂)₂(2,3-dihydro-1H-inden-2-yl), —(CH₂)₃C(═O) (2-NH₂-phenyl), —(CH₂)₃C(═O)(2-NH₂-5-F-phenyl), —(CH₂)₃C(═O) (2-NH₂-4-F-phenyl), —(CH₂)₃C(═O)(2-NH₂-3-F-phenyl), —(CH₂)₃C(═O) (2-NH₂-4-Cl-phenyl), —(CH₂)₃C(═O)(2-NH₂-4-OH-phenyl), —(CH₂)₃C(═O) (2-NH₂-4-Br-phenyl),—(CH₂)₃(1H-indazol-3-yl), —(CH₂)₃(5-F-1H-indazol-3-yl),—(CH₂)₃(7-F-1H-indazol-3-yl), —(CH₂)₃(6-Cl-1H-indazol-3-yl),—(CH₂)₃(6-Br-1H-indazol-3-yl), —(CH₂)₃C(═O) (2-NHMe-phenyl),—(CH₂)₃(1-benzothien-3-yl), —(CH₂)₃(6-F-1H-indol-1-yl),—(CH₂)₃(5-F-1H-indol-1-yl), —(CH₂)₃(6-F-2,3-dihydro-1H-indol-1-yl),—(CH₂)₃(5-F-2,3-dihydro-1H-indol-1-yl), —(CH₂)₃(6-F-1H-indol-3-yl),—(CH₂)₃(5-F-1H-indol-3-yl) —(CH₂)₃(5-F-1H-indol-3-yl),—(CH₂)₃(9H-purin-9-yl), —(CH₂)₃(7H-purin-7-yl),—(CH₂)₃(6-F-1H-indazol-3-yl), —(CH₂)₃C(═O) (2-NHSO₂Me-4-F-phenyl),—(CH₂)₃C(═O) (2-NHC(═O)Me-4-F-phenyl), —(CH₂)₃C(═O)(2-NHC(═O)Me-4-F-phenyl), —(CH₂)₃C(═O) (2-NHCO₂Et-4-F-phenyl),—(CH₂)₃C(═O) (2-NHC(═O)NHEt-4-F-phenyl), —(CH₂)₃C(═O)(2-NHCHO-4-F-phenyl), —(CH₂)₃C(═O) (2-OH-4-F-phenyl), —(CH₂)₃C(═O)(2-MeS-4-F-phenyl), —(CH₂)₃C(═O) (2-NHSO₂Me-4-F-phenyl),—(CH₂)₂C(Me)CO₂Me, —(CH₂)₂C(Me)CH(OH) (4-F-phenyl)₂ —(CH₂)₂C(Me)CH(OH)(4-Cl-phenyl)₂, —(CH₂)₂C(Me)C(═O) (4-F-phenyl), —(CH₂)₂C(Me)C(═O)(2-MeO-4-F-phenyl) —(CH₂)₂C(Me)C(═O) (3-Me-4-F-phenyl),—(CH₂)₂C(Me)C(═O) (2-Me-phenyl), —(CH₂)₂C(Me)C(═O) phenyl,

R⁷, R⁸, and R⁹, at each occurrence, are independently selected fromhydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,isopropoxy, trifluoromethoxy, methylCO(═O)—, ethylC(═O)—, propylC(═O)—,isopropylC(═O)—, methylC(═O)NH—, ethylC(═O)NH—, propylC(═O)NH—,isopropylC(═O)NH, methylamino-, ethylamino-, propylamino-, andisopropylamino-, provided that two of substituents R⁷, R⁸, and R⁹, areindependently selected from hydrogen, fluoro, chloro, methyl,trifluoromethyl, methoxy, and trifluoromethoxy; R^(10A) is selected fromhydrogen, methyl, ethyl, propyl, isopropyl, butyl, benzyl,2-chlorobenzyl, 2-fluorobenzyl, 2-bromobenzyl, 2-methylbenzyl,2-trifluoromethylbenzyl, 2-methoxybenzyl, 2-trifluoromethoxybenzyl,3-chlorobenzyl, 3-fluorobenzyl, 3-bromobenzyl, 3-methylbenzyl,3-trifluoromethylbenzyl, 3-methoxybenzyl, 3-trifluoromethoxybenzyl,4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl,4-trifluoromethylbenzyl, 4-methoxybenzyl, and 4-trifluoromethoxybenzyl;m is 1 or 2; and n is 1 or
 2. 15. A compound of selected from the groupconsisting of4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-pyridinyl)-1-butanonehydrochloride;(6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;(6bR,10aS)-8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride;(6bR,10aS)-8-[3-(1,2-benzisoxazol-3-yl)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride; (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-ethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-propyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-ispropyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-butyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-3-benzyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;4-((6bR,10aS)-3-ethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;4-((6bR,10aS)-3-isopropyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;4-((6bR,10aS)-3-benzyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;(6bR,10aS)-8-[3-(4-fluorophenoxy)propyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline;(6bR,10aS)-5-(2,4-dichlorophenyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalinehydrochloride;4-((6bR,10aS)-5-bromo-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;4-((6bR,10aR)-5-methoxy-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone;(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indolehydrochloride;(8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydro[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indolehydrochloride;(6bS,11aS)-3-methyl-2,3,7,8,9,10,11,11a-octahydro-1H,6bH-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline;4-(3-methyl-2,3,6b,7,8,10,11,11a-octahydro-1H,9H-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxalin-9-yl)-1-(4-fluorophenyl)-1-butanone;and(+/−)−1,1,3-Trimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline.16. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, or apharmaceutically acceptable salt thereof.
 17. A method for treating ahuman suffering from a disorder associated with 5HT2C receptormodulation selected from obesity, anorexia, bulemia, depression, aanxiety, psychosis, schizophrenia, migraine, obsessive-compulsivedisorder, and sexual disorders; comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of claim1, 2, 3, 4, 5, 6, 7, or 8 or a pharmaceutically acceptable salt thereof.18. A method for treating a human suffering from a disorder associatedwith 5HT2A receptor modulation selected from depression, psychosis,schizophrenia, migraine, attention deficit disorder, attention deficithyperactivity disorder, and obsessive-compulsive disorder; comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1, 9, 10, 11, 12, 13, or 14; or apharmaceutically acceptable salt thereof.
 19. A method for treatingobesity comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1, 2, 3, 4, 5,6, 7, or 8, or a pharmaceutically acceptable salt thereof.
 20. A methodfor treating schizophrenia comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, or a pharmaceuticallyacceptable salt thereof.
 21. A method for treating depression comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,or 14, or a pharmaceutically acceptable salt thereof.